Conjugates activated by cell surface proteases and therapeutic uses thereof

ABSTRACT

Conjugates, compositions and methods for treatment, prevention, or amelioration of one or more symptoms of cell surface protease-related diseases, including MTSP-related, urokinase-type plasminogen activator (uPA) or endotheliase-related diseases, are provided. The conjugates for use in the compositions and methods are peptidic conjugates that contain therapeutic, including cytotoxic, agents.

RELATED APPLICATIONS

[0001] Benefit of priority under 35 U.S.C. §119(e) to U.S. provisionalapplication Serial No. 60/293,267, filed May 23, 2001, to Edwin L.Madison, Joseph Edward Semple and George P. Vlasuk, entitled “CONJUGATESACTIVATED BY CELL SURFACE PROTEASES AND THERAPEUTIC USES THEREOF” isclaimed. The subject matter of the above-referenced application isincorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] Conjugates, compositions and methods for localized delivery oftherapeutic agents for treating a variety of disorders, such as,proliferative diseases, autoimmune diseases, infectious diseases andinflammatory diseases, are provided. The conjugates, which act asprodrugs, contain therapeutic agents and peptidic substrates that arecleaved by cell surface proteases to release therapeutic agents in thevicinity of the targeted cells.

BACKGROUND

[0003] Effective treatment of cancer and other proliferative diseasesinvolves administration of chemotherapeutic agents, typically systemicadministration. Typically chemotherapeutic agents are cytotoxic agentsthat act by inhibiting proliferation or other metabolic processes, sothat actively proliferating and growing cells will be targeted by theagent. Such targeting, however, is not highly specific, and theside-effects are often devastating.

[0004] Thus, a goal in pharmacology is the design of specific agentsthat act with high specific activity on targeted cells or tissues. Thisaim is of particular importance, for example, in the design of agentsfor treatments of diseases, such as proliferative diseases, includingneoplastic disease, and diseases of viral origin, in which the ratio oftoxic dose to therapeutic dose is generally close to one and the dosagemust be restricted. Numerous approaches to achieving this goal have beendeveloped. Among these are the use of conjugates that contain atargeting agent, such as an antibody and/or growth factor, and atherapeutic agent, that act on specific cells; the use of antisensetechnology that is targeted to specific genes and/or proteins; the useof genetic therapy to provide, for example, correct copies of defectivegenes or pharmaceutically active compounds, and the use of toxins thatare relatively non-toxic unless delivered intracellularly. Thus farsuccess has been limited. There are only a limited number and type ofpotential targeting agents, and the specificity of such agents isoptimal.

[0005] Hence there is a need to develop means for delivery oftherapeutic agents to targeted cells and tissues. Therefore, it is anobject herein, among others, to provide methods and compounds fortargeted delivery of therapeutic agents.

SUMMARY OF THE INVENTION

[0006] Provided herein are compounds and methods for targeted deliveryof therapeutic agents. The compounds are conjugates that contain apeptidic substrate for a cell surface protease, or a soluble, shed orreleased form thereof, and an agent that upon cleavage by the proteaseis a therapeutic agent or in a form that can be activated by thetargeted cell or tissue or in the localter thereof. The agents includetherapeutic agents, such as a cytotoxic agents, drugs, therapeuticnucleic acid moleulces, and diagnostic agents, such as labelled moietiesand imaging agents. The cell surface proteases are proteases located ata cell surface and, include, but are not limited to, membrane-boundproteases such as membrane-bound serine proteases (SPs), including, forexample, proteases designated MTSPs and endotheliases. Also contemplatedare proteases that are located at the cell surface by virtue of aspecific binding interaction with a receptor therefor. Included amongsuch proteases is urokinase plasminogen activator (u-PA; see, e.g., Hung(1984) Adv. Exp. Med. Biol. 172:281-293; Cheng et al. (1989) Gene69:357-363) bound to urokinase plasminogen activator receptor (u-PAR).

[0007] The conjugates contain one or more substrates for one or aplurality of cell surface proteases linked either directly or via alinker to a targeted agent, including a therapeutic agent, such as acytotoxic agent. The conjugates provided herein contain the followingcomponents: (peptidic substrate)_(s), (linker)_(q), and (targetedagent)_(t) in which: at least one peptidic substrate moiety is linkedwith or without a linker (L) to at least one therapeutic agent, s is 1or more and each substrate is the same or different, and is typically isbetween 1 and 6, generally 1, 2 or 3; q is 0 or more as long as cellsurface protease(s) cleaves the peptidic substrate(s) and releasesactive therapeutic agent or, releases the agent in a form that isconverted by the cell, tissue or surrounding environment to an activeform, q is 0 to t, generally 1 to 4; t is 1 or more, generally 1 or 2and each targeted agent are the same or different; linker refers to anylinker; and the targeted agent is any agent, typically a therapeuticagent, such as a cytotoxic agent, a nucleic acid, a diagnostic agent,such as an imaging agent or labeled moiety, or a drug, including, butnot limited to, anti-tumor, anti-cancer, anti-angiogenic, pro-apoptoticand anti-mitotic agents or treatments.

[0008] The therapeutic agents include any biologically active molecule.These agents include toxins, cytokines and lymphokines, growth factors,nucleic acid molecules, such as antisense nucleic acid, dsRNA, and DNAmolecules. The therapeutic agents include those that are activeintracellularly, such as cytotoxins, or extracellularly, such asmodulators of the activity of extracellular receptors. When in theconjugates the therapeutic agents are substantially inactive, and whencleaved are released in active form or in a form that can be activatedby the targeted cell or tissue or environment thereof.

[0009] In an exemplary embodiment, the conjugates for use in the methodsand compositions provided herein can be represented by the formula:

(peptide^(l))_(s)-(linker)_(q)-(therapeutic agent)_(t)

[0010] or a derivative thereof, where peptide^(l) is a peptidicsubstrate for a cell surface protease; s is greater than or equal to 1,or is 1 to 6, or is 1 or 2, or is 1; linker is any linker; q is greaterthan or equal to 0, or is 0 to 4, or is 0 or 1; the therapeutic agentis, for example, a cytotoxic agent, including, but not limited to, ananti-tumor, anti-angiogenic, anti-cancer, pro-apoptotic and anti-mitoticagents; and t is 1 or more, or is 1 or 2. In these conjugates, thetherapeutic agent is covalently attached, optionally via a linker L, toeither the C-terminus or the N-terminus of the peptidic substrate.

[0011] In certain embodiments, peptide^(l) is a substrate for a cellsurface protease whereby, upon action of the protease, the conjugate,which is substantially inactive, is cleaved at a point on the peptidicsubstrate chain to release a compound of the formula:

(peptide^(a))_(s)-(linker)_(q)-(therapeutic agent)_(t)

[0012] or a derivative thereof, that exhibits therapeutic activity invitro and/or in vivo. In these conjugates, the therapeutic agent is, forexample, a cytotoxic agent, and peptide^(a) is a truncated version ofpeptide^(l) resulting from cleavage at the P1-P1′ bond.

[0013] The conjugates can be used to target and deliver the targetedagents to specific cells, and hence can be used for the treatment anydiseases that are associated with cells or tissues that express a cellsurface protease, including cell-associated and cell-localizedproteases. The cells on which or near which such proteases are expressedare not necessarily involved in the disease or disease process, but arepresent and can serve to present the protease, which cleaves thetargeted conjugate.

[0014] Methods of treatment of diseases associated with cells or tissuesthat express a cell surface protease, including cell-associated andcell-localized proteases. The diseases include, but not limited to,proliferative diseases, autoimmune diseases, infectious diseases andinflammatory diseases. For example, diseases include e, but are notlimited to, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis,diabetic retinopathies, other ocular disorders, including recurrence ofpterygii, scarring excimer laser surgery and glaucoma filtering surgery,various disorders of the anterior eye, cardiovascular disorders,restenosis, chronic inflammatory diseases, wounds, circulatorydisorders, crest syndromes, bacterial infections, viral diseases,including AIDS, dermatological disorders, and cancer, including solidneoplasms and vascular tumors, including, but are not limited to, lung,colon, esophageal, breast, ovarian and prostate cancers.

[0015] Also provided are methods for identifying proteases to targetconjugates for treatment of diseases. The methods involve identifyingcell-surface protease-associated disease by identifying a cell involvedin the disease process or a cell in the vicinity of the cell involved inthe disease process; and identifying a cell surface protease on thecell. Conjugates that target such proteases as provided herein can thenbe prepared.

DESCRIPTION OF THE FIGURES

[0016] FIGS. 1-5 provide in vitro CT₅₀ (time for 50% cleavage) (min) forexemplary conjugates provided herein: A=0.1-25 min; B=25-100 min;C=100-250 min; D=>250 min.

[0017]FIG. 1 shows exemplary doxorubicin conjugates provided herein andin vitro CT₅₀ (min) data for cleavage of the conjugates by MTSP1.

[0018]FIG. 2 shows exemplary doxorubicin conjugates provided herein andin vitro CT₅₀ (min) data for cleavage of the conjugates by u-PA.

[0019]FIG. 3 shows exemplary taxol conjugates provided herein and invitro CT₅₀ (min) data for cleavage of the conjugates by MTSP1.

[0020]FIG. 4 shows exemplary taxol conjugates provided herein and invitro CT₅₀ (min) data for cleavage of the conjugates by u-PA.

[0021]FIG. 5 shows exemplary doxorubicin and taxol conjugates providedherein and in vitro CT₅₀ (min) data for cleavage of the conjugates byET1 (endotheliase 1).

DETAILED DESCRIPTION OF EMBODIMENTS A. Definitions

[0022] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as is commonly understood by one of skillin the art to which the invention(s) belong. All patents, patentapplications, published applications and publications, Genbanksequences, websites and other published materials referred to throughoutthe entire disclosure herein, unless noted otherwise, are incorporatedby reference in their entirety. In the event that there are a pluralityof definitions for terms herein, those in this section prevail. Wherereference is made to a URL or other such indentifier or address, itunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

[0023] As used herein, a targeted agent is any agent intended fortargeted delivery and includes therapeutic agents and diagnostic agentsand any other agent intended for targeted delivery.

[0024] As used herein, targeted delivery means delivery to a selectedcell or tissue that expresses a protease that releases the targetedagent. Such delivery does not have to be exclusively to such selectedcell or tissue, but must include it, and generally deliveries higheramounts to such selected cells or tissues. Delivery includesintroduction into a cell or tissue or binding to the cell or tissue orrelease in the vicinity of the cell or tissue. For example, in someinstances, a tumor induces production of proteases, receptors,co-factors or substrates asssociated with the stroma; delivery, thus,includes targeting such induced stromal activities, such as proteases,receptors and/or enzyme co-factors, in invading cells or cells in thetumor that is targeted.

[0025] As used herein, therapeutic index is the ratio of LD₅₀/ED₅₀.

[0026] As used herein, a therapeutic agent is any drug or other agentthat is intended for delivery to a targeted cell or tissue, such asproliferating cells, including tumor cells and cells involved in aproliferative, typically an undesirable, response. Therapeutic agents,include, but are not limited to, anti-cancer agents, anti-angiogenicagents, pro-apoptotic agents, anti-mitotic growth factors, cytokines,such as tumor necrosis factors and interleukins, and cytotoxic agentsand other such agents as described herein and known to those of skill inthe art. Therapeutic agents include those that are active uponinternalization and also those that act extracellularly, such modulatorsof the activities of certain cell surface receptors, such as G proteinsthat transduce extracellular signals.

[0027] As used herein, an inactive therapeutic agent is a therapeuticagent that is conjugated to a peptide and thereby, either by virtue ofconformational changes or size or other factors such as sterichinderance does not exhibit any or exhibits substantially reducedactivity compared to the released active therapeutic agent. For example,conjugated doxorubicin is not toxic to cells until it is released fromthe conjugate in a form that can enter the cell. Upon cleavage of theagent from the conjugate it is in active form or in a form that isfurther processed by one or a plurality of steps, includingenzymatically or chemically, in or on the cell, into an active form.

[0028] As used herein, an active therapeutic agent is a therapeuticagent that has been released from the conjugate by cleavage of thepeptidic substrate portion of the conjugate. The active therapeuticagent is by virtue of cleavage able to exhibit its intended activity,typically by entering the cell. When conjugated the therapeutic agentshave reduced or no activity as therapeutic agents, and upon cleavage arereleased in the vicinity of a cell.

[0029] As used herein, an anti-cancer agent (used interchangeably with“anti-tumor or anti-neoplasm agent”) refers to any agents used in thetreatment of cancer. These include any agents, when used alone or incombination with other compounds, that can alleviate, reduce,ameliorate, prevent, or place or maintain in a state of remission ofclinical symptoms or diagnostic markers associated with neoplasm, tumoror cancer, and can be used in methods, combinations and compositionsprovided herein. Non-limiting examples of anti-neoplasm agents includeanti-angiogenic agents, alkylating agents, antimetabolite, certainnatural products, platinum coordination complexes, anthracenediones,substituted ureas, methylhydrazine derivatives, adrenocorticalsuppressants, certain hormones, antagonists and anti-cancerpolysaccharides.

[0030] As used herein, substantially inactive with reference to theconjugated thereapeutic agent means at least 1%, generally 10, 20, 30,50, 60, 70, 80 or 90 or 100% inactive compared to the unconjugatedtherapeutic agent in a standard or art-recognized assays, such as invitro or in vivo assays, that assess the therapeutic activity of theagent.

[0031] As used herein, a targeted cell or tissue refers to the cells ortissues that include cell surface proteases that cleave the conjugates.The cells or tissues can be involved in the disease or can be present atthe disease loci or locus by virtue of participation in the diseaseprocess or merely serendipitously.

[0032] As used herein, angiogenesis is intended to broadly encompass thetotality of processes directly or indirectly involved in theestablishment and maintenance of new vasculature (neovascularization),including, but not limited to, neovascularization associated withtumors.

[0033] As used herein, anti-angiogenic treatment or agent refers to anytherapeutic regimen and compound, that, when used alone or incombination with other treatment or compounds, can alleviate, reduce,ameliorate, prevent, or place or maintain in a state of remission, oneor more clinical symptoms or diagnostic markers associated withundesired and/or uncontrolled angiogenesis. Thus, for purposes herein ananti-angiogenic agent refers to an agent that inhibits the establishmentor maintenance of vasculature. Such agents include, but are not limitedto, anti-tumor agents, and agents for treatments of other disordersassociated with undesirable angiogenesis, such as diabeticretinopathies, hyperproliferative disorders and others.

[0034] As used herein, non-anti-angiogenic anti-tumor agents refer toanti-tumor agents that do not act primarily by inhibiting angiogenesis.Whether anti-tumor agents act primarily by inhibiting angiogenesis canbe determined using the assays provided herein, or using other assayswell known to those of skill in the art.

[0035] As used herein, undesired and/or uncontrolled angiogenesis refersto pathological angiogenesis wherein the influence of angiogenesisstimulators outweighs the influence of angiogenesis inhibitors. As usedherein, deficient angiogenesis refers to pathological angiogenesisassociated with disorders where there is a defect in normal angiogenesisresulting in aberrant angiogenesis or an absence or substantialreduction in angiogenesis.

[0036] As used herein, a cell surface protease is any protease that islocated on or at a cell surface and/or proteases that are located at thecell surface by virtue of a specific binding interaction with a receptortherefor, or that is localized at or near or associated with the cellsurface. An exemplary protease located at the cell surface by virtue ofa specific binding interaction with a receptor therefor is urokinaseplasminogen activator (u-PA) bound to urokinase plasminogen activatorreceptor (u-PAR). Hence cell surface proteases contemplated hereininclude cell surface-associated proteases. It also includes all formsthereof that can be circulating or inside a cell. To be categorized as acell surface protease, there must be at least one form thereof that islocated (i.e. on the surfaces such as transmembrane protease or bound toreceptor therefor) on the surface of a cell at some point in its cycle.Cell surface protease include serine proteases, such as, but are notlimited to, the transmembrane serine protease (MTSPs) and endotheliasesand urokinases.

[0037] As used herein, a serine protease (SP) refers to a diverse familyof proteases in which a serine residue is involved in the hydrolysis ofproteins or peptides. The serine residue can be part of the catalytictriad mechanism, which includes a serine, a histidine and an asparticacid in the catalysis, or be part of the hydroxyl/ε-amine orhydroxyl/α-amine catalytic dyad mechanism, which involves a serine and alysine in the catalysis. Of particular interest are SPs of mammalian,including human, origin. Those of skill in this art recognize that, ingeneral, single amino acid substitutions in non-essential regions of apolypeptide do not substantially alter biological activity (see, e.g.,Watson et al. (1987) Molecular Biology of the Gene, 4th Edition, TheBejacmin/Cummings Pub. co., p.224).

[0038] As used herein shed, soluble and released forms of cell surfaceproteases are contemplated. Such forms include, for example, forms foundin serum upon proteolytic degradation or other removal of theextracellular portion of membrane bound protease, and splice variantsthat do not include a transmembrane domain.

[0039] As shown herein, the protease activity of cell surface proteasesand proteases associated with cells can be exploited to provide a meansto concentrate therapeutic agents, such as cytotoxic agents, near suchcells by providing conjugates that are activated upon cleavage by suchenzymes. Such conjugates, upon the action of a cell surface protease orcell-associate protease, release the therapeutic agent, such as acytotoxic agent, or a derivative thereof that can be converted to atherapeutic agent, locally at the site of action. As noted above, thesubstrates are designed to be substrates of targeted proteases that areexpressed or are active on the surfaces of cells, such as tumor cells orendothelial cells, involved in or present at the site(s) or locus orloci of the disease. By virtue of specific expression, localization oractivation of such proteases or the presence of receptors, substrates orenzyme co-factors therefor, administration of the conjugates providedherein permits targeting of therapeutic agents to such cells. Uponcontacting with the proteases, active therapeutic agents are released inthe immediate vicinity of the targeted cells. For example, specificprofiles of some of the MTSPs are as follows.

[0040] As used herein, “transmembrane serine protease (MTSP)” refers toa family of transmembrane serine proteases that share common structuralfeatures as described herein (see, also Hooper et al. (2001) J. Biol.Chem.276:857-860). Thus, reference, for example, to “MTSP” encompassesall proteins encoded by the MTSP genes, including but are not limitedto: MTSP1, MTSP3, MTSP4, MTSP6, MTSP7, MTSP9, MTSP10, MTSP12, MTSP20,MTSP22 and MTSP25 or an equivalent molecule obtained from any othersource or that has been prepared synthetically or that exhibits the sameactivity. Other MTSPs include, but are not limited to, corin,enteropeptidase, human airway trypsin-like protease (HAT), TMPRSS2 andTMPRSS4. The MTSPs described herein can be used to identify other MTSPs.Methods for isolating nucleic acid encoding other MTSPs, includingnucleic acid molecules encoding full-length molecules and splicevariants and MTSPs from species, such as cows, sheep, goats, pigs,horses, primates, including chimpanzees and gorillas, rodents, dogs,cats and other species of interest, such as domesticated animals, farmand zoo animals are known to those of skill in the art and are outlinedherein. The nucleic acid molecules described herein including those setforth in SEQ IDs can be used to obtain nucleic acid molecules encodingfull-length MTSP polypeptides from human sources or from other species,such as by screening appropriate libraries using the nucleic acidmolecules or selected primers or probes based thereon.

[0041] Sequences of encoding nucleic acid molecules and the encodedamino acid sequences of exemplary MTSPs and/or domains thereof are setforth in SEQ ID Nos. 1-45, 269-270 and 272-276. The term alsoencompasses MTSPs with amino acid substitutions that do notsubstantially alter activity of each member and also encompassespolyeptides encoded by splice variants thereof. Hence, encompassed areMTSPs with amino acid substitutions such that the resulting polypeptideretains at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ofthe proteolytic activity of the unaltered polypeptide, and alsoencompasses MTSPs encoded by splice variants thereof and MTSPs encodedby allelic variants, such as single nucleotide polymorphisms (SNPs).Suitable substitutions, including, although not necessarily,conservative substitutions of amino acids, are known to those of skillin this art and can be made without eliminating the biological activity,such as the catalytic activity, of the resulting molecule. MTSPs includethose of animal, such as mammalian, including human, origin.

[0042] As used herein, a “protease domain of an MTSP” refers to anextracellular protease domain of an MTSP that exhibits proteolyticactivity and shares homology and structural features with thechymotryp-sin/trypsin family protease domains. Hence it is at least theminimal portion of the domain that exhibits proteolytic activity asassessed by standard in vitro assays. Contemplated herein are suchprotease domains and catalytically active portions thereof.

[0043] Exemplary MTSP polypeptides, with the protease domains indicated,are set forth in SEQ ID Nos. 1-45, 269-270 and 272-276, and includingsmaller portions thereof that retain or exhibit protease activity. Theprotease domains vary in size and constitution, including insertions anddeletions in surface loops. They retain conserved structure, includingat least one of the active site triad, primary specificity pocket,oxyanion hole and/or other features of serine protease domains ofproteases. Thus, for purposes herein, the protease domain is a portionof a MTSP, as defined herein, and is homologous to a domain of otherMTSPs. MTSPs include, MTSP1, MTSP3, MTSP4, MTSP6, MTSP7, MTSP9, MTSP10,MTSP12, MTSP20, MTSP22 and MTSP25 (see SEQ ID Nos. 1-19, 42-45, 269-270and 272-276; see, also International PCT application No. WO 02/00860(see SEQ ID Nos. 38 and 97 therein, which provide an MTSP12 variant);corin (SEQ ID Nos. 28 and 29), enteropeptidase (SEQ ID Nos. 30 and 31)human airway trypsin-like protease (HAT) (SEQ ID Nos. 32 and 33), hepsin(SEQ ID Nos. 34 and 35), TMPRSS2 (SEQ ID Nos. 36 and 37) and TMPRSS4(SEQ ID Nos. 38 and 39). As with the larger class of enzymes of thechymotrypsin (S1) fold (see, e.g., Internet accessible MEROPS database), the MTSPs protease domains share a high degree of amino acidsequence identity. The His, Asp and Ser residues necessary for activityare present in conserved motifs. In those that are activated bycleavage, the activation site, which results in the N-terminus of secondchain in the two chain forms has a conserved motif and readily can beidentified (see, e.g., amino acids 801-806, SEQ ID No. 29, amino acids406-410, SEQ ID No. 31; amino acids 186-190, SEQ ID No. 33; amino acids161-166, SEQ ID No. 35; amino acids 255-259, SEQ ID No. 37; amino acids190-194, SEQ ID No. 39 and other as known to those of skill and the artand/or as described herein).

[0044] For example, with reference to MTSP10 (see SEQ ID Nos. 44 and45), there disulfide bonds as follows: C₄₈₈-C₅₀₄, C₅₈₇-C₆₅₃; C₆₁₉-C₆₃₂;C₆₄₃-C₆₇₃ (see SEQ ID Nos. 44 and 45) (chymotrypsin numbering 42 to 58;136-201; 168-182 and 191-220). Disulfide bonds form between the Cysresidues C₅₇₃-C₂₉₆ to link the protease domain to another domain so thatupon activation cleavage (between residues R₄₆₂ and I₄₆₃ of SEQ ID No.45) the resulting polypeptide is a two chain molecule. The C₅₇₃ (SEQ IDNO. 45 is a free Cys in a single chain form of the protease domain. Asnoted the protease also can be provided as a two chain molecule. Singlechain and two chain forms are proteolytically active. A two chain formis produced by bonding, typically between the C₅₇₃ and a Cys outside theprotease domain, such as Cys₂₉₆. Upon activation cleavage the disulfidebond remains resulting in a two chain polypeptide. The size of chain “A”is a function the starting length of the polypeptide prior to activationcleavage between the R₄₆₂ and I₄₆₃. Any length polypeptide that includesthe protease domain (residues 463-692 of SEQ ID No. 45) or catalyticallyactive fragments thereof, is contemplated herein. Two chain formsinclude at least the protease domain a polypeptide from C₂₉₆ up to andincluding C₅₇₃.

[0045] As used herein, a two-chain form of the protease domain refers toa two-chain form that is formed from a single chain form of the proteasein which the Cys pairing between, e.g., a Cys outside the proteasedomain such as, for example Cys₅₇₃ (SEQ ID No. 45 for MTSP), which linksthe protease domain to the remainder of the polypeptide, the “A” chain.A two chain protease domain form refers to any form in which the“remainder of the polypeptide”, i.e., “A” chain, is shortened andincludes a Cys from outside the protease domain.

[0046] As used herein, the catalytically active domain of an MTSP refersto the protease domain. Reference to the protease domain of an MTSPgenerally refers to a single chain form of the protein. If the two-chainform or both forms is intended, it is so-specified. The zymogen form ofeach protein is a single chain, which is converted to the active two ormulti chain form by activation cleavage. By active form is meant a formactive in vivo or in vitro.

[0047] As used herein, activation cleavage refers to the cleavage of theprotease at the N-terminus of the protease domain (generally between anR and I or V in the full-length protein. By virtue of the Cys-Cyspairing between a Cys outside the protease domain and a Cys in theprotease domain (see, e.g., Cys₅₇₃ SEQ ID No. 45, upon cleavage theresulting polypeptide has two chains (“A” chain and the “B” chain, whichis the protease domain of an MTSP). Cleavage can be effected by anotherprotease or autocatalytically. The conjugates provided hereinadvantageously contain sites that are recognized by the active cellsurface protease (or cell-associated protease) and are cleaved therebyto release active or an inactive prodrug form of a therapeutic agent.

[0048] As used herein an MTSP1, whenever referenced herein, includes atleast one or all of or any combination of:

[0049] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 1 or 40;

[0050] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 1 or 40;

[0051] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 2 or 41;

[0052] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 2 or41; and/or

[0053] a polypeptide encoded by a splice variant of the MTSP1 set forthin SEQ ID No. 1 or 40.

[0054] The MTSP1 can be from any animal, particularly a mammal, andincludes but is not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form. MTSP1 also isreferred to TADG-15 and matriptase. As described below, the proteinoriginally designated matriptase appears to be an MTSP1 splice variantor processed product.

[0055] As used herein an MTSP3, whenever referenced herein, includes atleast one or all of or any combination of:

[0056] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 3;

[0057] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 3;

[0058] a polypeptide that comprises the sequence of amino acids setforth as amino acids 205-437 of SEQ ID No. 4;

[0059] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 4;and/or

[0060] a polypeptide encoded by a splice variant of the MTSP3 set forthin SEQ ID Nos. 3 and 4.

[0061] The MTSP3 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form.

[0062] As used herein an MTSP4, whenever referenced herein, includes atleast one or all of or any combination of:

[0063] a polypeptide encoded by the sequence of nucleotides set forth inany of SEQ ID No. 5, 7 or 9;

[0064] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in any of SEQ ID Nos. 5, 7 or 9;

[0065] a polypeptide that comprises the sequence of amino acids setforth in any of SEQ ID Nos. 6, 8 or 10;

[0066] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 6, 8or 10; and/or

[0067] a polypeptide encoded by a splice variant of the MTSP4s set forthin SEQ ID Nos. 7-10.

[0068] The MTSP4 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form.

[0069] As used herein an MTSP6, whenever referenced herein, includes atleast one or all of or any combination of:

[0070] a polypeptide encoded by the sequence of nucleotides set forth inany of SEQ ID No. 11;

[0071] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in any of SEQ ID Nos. 11;

[0072] a polypeptide that comprises the sequence of amino acids setforth in any of SEQ ID No. 12;

[0073] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 12;and/or

[0074] a polypeptide encoded by a splice variant of the MTSP6 set forthin SEQ ID No. 12.

[0075] The MTSP6 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form. Of particularinterest herein is the MTSP6 of SEQ ID No. 12.

[0076] As used herein an MTSP7, whenever referenced herein, includes atleast one or all of or any combination of:

[0077] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 13;

[0078] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 13;

[0079] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 13;

[0080] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 14;and/or

[0081] a polypeptide encoded by a splice variant of the MTSP7 set forthin SEQ ID No. 13.

[0082] The MTSP7 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form.

[0083] As used herein an MTSP9, whenever referenced herein, includes atleast one or all of or any combination of:

[0084] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 17 or SEQ ID No. 42;

[0085] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 17 or 42;

[0086] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 18 or 43;

[0087] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 18 or270; and/or

[0088] a polypeptide encoded by a splice variant of the MTSP9 set forthin SEQ ID No. 17.

[0089] The MTSP9 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form.

[0090] As used herein an MTSP10, whenever referenced herein, includes atleast one or all of or any combination of:

[0091] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 44;

[0092] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 44;

[0093] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 45;

[0094] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 45;and/or

[0095] a polypeptide encoded by a splice variant of the MTSP10 set forthin SEQ ID No. 44.

[0096] The MTSP10 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two chain activated form, or a single chain form.

[0097] MTSP10 polypeptides, including, but not limited to splicevariants thereof, and nucleic acids encoding MTSPs, and domains,derivatives and analogs thereof are provided herein. Single chainprotease domains that have an N-terminus functionally equivalent to thatgenerated by activation of the zymogen form of MTSP10 are also provided.The cleavage site for the protease domain of MTSP10 is between aminoacid R and amino acids I (R↓IIGGT) (residues 462-467 SEQ ID No. 45).

[0098] As used herein an MTSP12, whenever referenced herein, includes atleast one or all of or any combination of: SEQ ID No. 19 and 20

[0099] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 19 or by a sequence of nucleotides that includes nucleotidesthat encode the sequence of amino acids set forth in SEQ ID No. 20;

[0100] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in is set forth as SEQ ID No. 19;

[0101] a polypeptide that includes the sequence of amino acids set forthin SEQ ID No. 20 or a catalytically active portion thereof;

[0102] a polypeptide that includes a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 20;and/or

[0103] a polypeptide encoded by a splice variant of the MTSP12 thatincludes the sequence of amino acids set forth in SEQ ID No. 20.

[0104] In particular, the MTSP12 polypeptide, with the protease domainsas indicated in SEQ ID Nos. 19 and 20, is provided. The polypeptide is asingle or multi-chain polypeptide. A protease domain of an MTSP12,whenever referenced herein, includes at least one or all of or anycombination of or a catalytically active portion of:

[0105] a polypeptide that includes the sequence of amino acids set forthin SEQ ID No. 20 or a catalytically active portion thereof but that doesnot include the sequence of amino acids set forth in SEQ ID No. 271;

[0106] a polypeptide that includes the sequence of amino acids set forthin SEQ ID No. 272 or a catalytically active fragment thereof;

[0107] a polyeptide containing amino acids 237 to 456 of SEQ ID No. 6, apolypeptide containing amino aicds 538 to 765 of SEQ ID No. 20, and apolypeptide containing amino acids 861 to 1087 of SEQ ID No. 20, butthat does not include the sequence of amino acids set forth in SEQ IDNo. 271;

[0108] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to asequence of nucleotides that encodes any of the polypeptides of a)-c);

[0109] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 20 but that does notencode the sequence of amino acids set forth in SEQ ID No. 271;

[0110] a polypeptide that includes a sequence of amino acids having atleast about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 20;

[0111] a polypeptide that includes a sequence of amino acids having atleast about 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids of the polypeptides of a)-e);

[0112] a polypeptide encoded by a splice variant of a sequence ofnucleotides that encodes an MTSP12 of any of the above.

[0113] Smaller portions thereof that retain protease activity are alsoprovided. The MTSP12 can be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full-length zymogen or two-chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two-chain activated form, or a single chain form. MTSP12 alsoincludes the variant described International PCT application No. WO02/00860 (see SEQ ID Nos. 38 and 97 therein).

[0114] As used herein an MTSP20, whenever referenced herein, includes atleast one or all of or any combination of:

[0115] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 273;

[0116] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 273;

[0117] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 273;

[0118] a polypetide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 274;and/or a polypeptide encoded by a splice variant of the MTSP20 encodedby the sequence of nucleotides that includes the sequence set forth inSEQ ID No. 273.

[0119] The MTSP20 may be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two-chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two-chain activated form, or a single chain form.

[0120] As used herein an MTSP22, whenever referenced herein, includes atleast one or all of or any combination of:

[0121] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 275;

[0122] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 275;

[0123] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 276;

[0124] a polypetide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 276;and/or

[0125] a polypeptide encoded by a splice variant of the MTSP22 set forthin SEQ ID No. 275.

[0126] The MTSP22 may be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two-chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two-chain activated form, or a single chain form.

[0127] As used herein an MTSP25, whenever referenced herein, includes atleast one or all of or any combination of:

[0128] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 269;

[0129] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 269;

[0130] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 270;

[0131] a polypetide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 270;and/or

[0132] a polypeptide encoded by a splice variant of the MTSP25 set forthin SEQ ID No. 269.

[0133] The MTSP25 may be from any animal, particularly a mammal, andincludes but are not limited to, humans, rodents, fowl, ruminants andother animals. The full length zymogen or two-chain activated form iscontemplated or any domain thereof, including the protease domain, whichcan be a two-chain activated form, or a single chain form.

[0134] As used herein, a human protein is one encoded by nucleic acidpresent in the genome of a human, including all allelic variants andconservative variations as long as they are not variants found in othermammals.

[0135] As used herein, not substantially cleaved by plasmin or prostatespecific antigen (PSA) (or other non-cell surface-associated protease),means in comparable in vitro assays (under optimal conditions for eachenzyme) in which the activity of a targeted cell surface membraneprotease or catalytically active portion of the activity of the proteasedomain (or a catalytically active form thereof) of prostate specificantigen (PSA) or plasmin for cleavage of the conjugate is compared, therelative activity is greater than at least 2:1, 3:1, 4:1, 5:1, 10:1,50:1 or 100:1.

[0136] As used herein, activity refers to the ratio k_(cat)/K_(m), wherek_(cat) is the rate of catalytic turnover for a particular enzyme, andK_(m) is the Michaelis constant for the binding of the substrate.

[0137] As used herein, a “nucleic acid encoding a protease domain orcatalytically active portion of a MTSP” shall be construed as referringto a nucleic acid encoding only the recited single chain protease domainor active portion thereof, and not the other contiguous portions of theMTSP as a continuous sequence.

[0138] As used herein, a CUB domain is a motif that mediatesprotein-protein interactions in complement components C1r/C1s and hasalso been identified in various proteins involved in developmentalprocesses.

[0139] As used herein, a zymogen is an enzymatically inactive protein(i.e, typically, but not necessarily, less than 1% of active form) thatis converted to a proteolytic enzyme by the action of an activator,including by autoactivation. Inactive means less active than the formthose of skill in the art consider to be the active form of the enzyme.The ratio of activity of a zymogen to the activated form varies fromenzyme-to-enzyme.

[0140] As used herein, “disease or disorder” refers to a pathologicalcondition in an organism resulting from, e.g., infection or geneticdefect, and characterized by identifiable symptoms. The diseasescontemplated for treatment herein are any for which a cell surfaceprotease, including a cell-localized or cell-associated protease isasssociated with a targeted cell or tissue involved in the disease ordisease process. Such association can be because the protease isinvolved in the disease or is serendipitously associated with cellsinvolved with the disease. These diseases herein are called cell surfaceprotease-associated diseases. Hence, to treat th disease a cellsurfaceprotease is identified that is expressed on cells associated with thedisorder, such as, for example, immune cells for treating inflammatorydiseases, and virally infected cells for treating viral diseases. Theconjugate is designed as described herein for cleavage by the selectedprotease.

[0141] As used herein, neoplasm (neoplasia) refers to abnormal newgrowth, and thus means the same as tumor, which can be benign ormalignant. Unlike hyperplasia, neoplastic proliferation persists even inthe absence of the original stimulus.

[0142] As used herein, neoplastic disease refers to any disorderinvolving cancer, including tumor development, growth, metastasis andprogression.

[0143] As used herein, cancer refers to a general term for diseasescaused by any type of malignant tumor.

[0144] As used herein, malignant, as applied to tumors, refers toprimary tumors that have the capacity of metastasis with loss of growthcontrol and positional control.

[0145] As used herein, endotheliase refers to a mammalian protein,including human protein, that has a transmembrane domain and isexpressed or active on the surface of endothelial cells and includes aprotease domain, particularly an extracellular protease domain, and isgenerally a serine protease (see, also U.S. application Ser. No.09/717,473 and International PCT application No. WO 01/36604). Thus,reference, for example, to endotheliase encompasses all proteins encodedby the endotheliase gene family, or an equivalent molecule obtained fromany other source or that has been prepared synthetically or thatexhibits the same activity. The endotheliase gene family aretransmembrane proteases expressed or active in endothelial cells. Theseproteases include serine proteases. These include proteins that havethese features and also include a protease domain that exhibits sequencehomology to the endotheliases 1 and 2. Endotheliase 1 and 2, for exampleexhibit about 40% or 45% identity. Sequence homology means sequenceidentity along its length when aligned to maximize identity of at leastabout 25%, 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or greaternumber of residues. Sequence homology also is assessed by determiningwhether the encoding sequences of nucleic acids hybridize underconditions of at least moderate, or for more closely related proteins,high stringency to the nucleic acid molecules provided herein or tothose that encode the same proteins but differ in sequence by virtue ofthe degeneracy of the genetic code. In addition, “endotheliases”encompasses endotheliases with amino acid substitutions, including thoseset forth in Table 1, such that the resulting polypeptide retains atleast 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of theproteolytic activity of the unaltered polypeptide. Suitablesubstitutions of amino acids are known to those of skill in this art andcan be made generally without altering the biological activity of theresulting molecule. As noted, those of skill in this art recognize that,in general, single amino acid substitutions in non-essential regions ofa polypeptide do not substantially alter biological activity (see, e.g.,Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, TheBejacmin/Cummings Pub. Co., p.224). Also included within the definitionof “endotheliases”, is the catalytically active fragment or shed formsof an endotheliase.

[0146] As used herein an endotheliase 1, whenever referenced herein,includes at least one or all of or any combination of:

[0147] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 21;

[0148] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 21;

[0149] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 22;

[0150] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 22;and/or

[0151] a polypeptide encoded by a splice variant of a nucleic acidmolecule that encodes a protein containing the polypeptide set forth inSEQ ID No. 22.

[0152] The endotheliase 1 can be from any animal, particularly a mammal,and includes but are not limited to, humans, rodents, fowl, ruminantsand other animals. The full length zymogen or two chain activated formis contemplated or any domain thereof, including the protease domain,which can be a two chain activated form, or a single chain form.

[0153] As used herein an endotheliase 2, whenever referenced herein,includes at least one or all of or any combination of:

[0154] a polypeptide encoded by the sequence of nucleotides set forth inSEQ ID No. 23 or 25;

[0155] a polypeptide encoded by a sequence of nucleotides thathybridizes under conditions of low, moderate or high stringency to thesequence of nucleotides set forth in SEQ ID No. 23 or 25;

[0156] a polypeptide that comprises the sequence of amino acids setforth in SEQ ID No. 24 or 26;

[0157] a polypeptide that comprises a sequence of amino acids having atleast about 40%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity with the sequence of amino acids set forth in SEQ ID No. 24 or26; and/or

[0158] a polypeptide encoded by a splice variant of a nucleic acid setforth in SEQ ID No. 23 or 25.

[0159] The endotheliase 2 can be from any animal, particularly a mammal,and includes but are not limited to, humans, rodents, fowl, ruminantsand other animals. The full length zymogen or two chain activated formis contemplated or any domain thereof, including the protease domain,which can be a two chain activated form, or a single chain form.

[0160] As used herein, the protease domain of an endotheliase refers tothe polypeptide portion of the endotheliase that is the extracellularportion that exhibits protease activity. The protease domain is apolypeptide that includes at least the minimum number of amino acids,generally more than 50 or 100, required for protease activity. Proteaseactivity can be assessed empirically, such as by testing the polypeptidefor its ability to act as a protease. Assays, such as those described inthe EXAMPLES, with the exception that a known endotheliase substrate isemployed in place of the test compounds, can be used to assess proteaseactivity. Furthermore, since proteases, particularly serine proteases,have characteristic structures and sequences or motifs, the proteasedomain can be readily identified by such structure and sequence ormotif.

[0161] As used herein, a portion of protease domain of endotheliaserefers to a portion of protease domain of endotheliase that is locatedwithin or is the extracellular domain of an endotheliase and exhibitsserine proteolytic activity. Hence, it is at least the minimal portionof the extracellular domain that exhibits proteolytic activity asassessed by standard assays. An exemplary protease domain of anendotheliase is set forth in SEQ ID No. 22 and as amino acids 321-688and 321-562 of SEQ ID Nos. 24 and 26, respectively. Smaller portionsthereof that retain protease activity are contemplated. The proteasedomains vary in size and constitution, including insertions anddeletions in surface loops. Such domains exhibit conserved structure,including at least one structural feature, such as the active sitetriad, primary specificity pocket, oxyanion hole and/or other featuresof serine protease domains of proteases. Thus, for purposes herein, theprotease domain is a portion of an endotheliase, as defined herein, butis homologous in terms of structural features and retention of sequenceof similarity or homology the protease domain of chymotrypsin ortrypsin.

[0162] As used herein, homologous means about greater than about 25%,40%, 60%, 80%, 90%, 95%, 98% or greater sequence identity. By sequenceidentity, the number of conserved amino acids as determined by standardalignment algorithms programs, and used with default gap penaltiesestablished by each supplier. Also homology can be assessed by conservednucleic acid sequence, which includes anything that hybridizes under atleast low stringency conditions and encodes the domain. Similarly,nucleic acid sequence alignment programs are commercially available(DNAStar “MegAlign” program (Madison, Wis.) and the University ofWisconsin Genetics Computer Group (UWG) “Gap” program (Madison, Wis.)).Substantially homologous nucleic acid molecules would hybridizetypically at moderate stringency or at high stringency all along thelength of the nucleic acid of interest. Also contemplated are nucleicacid molecules that contain degenerate codons in place of codons in thehybridizing nucleic acid molecule.

[0163] As used herein, recitation that a polypeptide consistsessentially of the protease domain means that the only endotheliaseportion of the polypeptide is a protease domain or a catalyticallyactive portion thereof. The polypeptide can optionally includeadditional non-endotheliase-derived sequences of amino acids.

[0164] As used herein, domain refers to a portion of a molecule, e.g.,proteins or nucleic acids, that is structurally and/or functionallydistinct from other portions of the molecule.

[0165] As used herein, an active form of a protease refers to an enzymethat catalyzes hydrolysis of proteins or peptides. Reference to aprotease includes the active and zymogen or other less active form.

[0166] As used herein, nucleic acids include DNA, RNA and analogsthereof, including peptide nucleic acids (PNA) and mixtures thereof.Nucleic acids can be single or two stranded. When referring to probes orprimers, optionally labeled, with a detectable label, such as afluorescent or radiolabel, single-stranded molecules are contemplated.Such molecules are typically of a length such that their targets arestatistically unique or of low copy number (typically less than 5,generally less than 3) for probing or priming a library. Generally aprobe or primer contains at least 14, 16 or 30 contiguous of sequencecomplementary to or identical to a gene of interest. Probes and primerscan be 10, 20, 30, 50, 100 or more nucleic acids long.

[0167] As used herein, nucleic acid encoding a fragment or portion of anendotheliase refers to a nucleic acid encoding only the recited fragmentor portion of endotheliase protein, and not the other contiguousportions of the endotheliase as a continuous sequence.

[0168] As used herein, heterologous nucleic acid is nucleic acid that,if it is DNA encodes RNA, or, if RNA, encodes proteins that generallyare not normally produced in vivo by the cell in which it is expressedor that mediates or encodes mediators that alter expression ofendogenous nucleic acid, such as DNA, by affecting transcription,translation, or other regulatable biochemical processes or that islocated in a different locus from its normal locus. Heterologous nucleicacid is generally not endogenous to the cell into which it isintroduced, but has been obtained from another cell or preparedsynthetically. Generally, although not necessarily, such nucleic acidencodes RNA and proteins that are not normally produced by the cell inwhich it is now expressed.

[0169] Heterologous nucleic acid, such as DNA, also be referred to asforeign nucleic acid, such as DNA. Any nucleic acid, such as DNA, thatone of skill in the art would recognize or consider as heterologous orforeign to the cell in which is expressed is herein encompassed byheterologous nucleic acid; heterologous nucleic acid includesexogenously added nucleic acid that is also expressed endogenously.Examples of heterologous nucleic acid include, but are not limited to,nucleic acid that encodes traceable marker proteins, such as a proteinthat confers drug resistance, nucleic acid that encodes therapeuticallyeffective substances, such as anti-cancer agents, enzymes and hormones,and nucleic acid, such as DNA, that encodes other types of proteins,such as antibodies, and RNA, such as RNA interference (RNAi) or otherdouble-stranded RNA, and antisense RNA. Antibodies that are encoded byheterologous nucleic acid can be secreted or expressed on the surface ofthe cell in which the heterologous nucleic acid has been introduced.

[0170] For example, nucleic acid can be the the targeted agent, such asthe therapeutic or diagnostic agent, in the conjugate. Nucleic acids,include ds RNA use for RNA interference (RNAi) (see, e.g. Chuang et al.(2000) Proc. Natl. Acad. Sci. U.S.A. 97:4985) which is employed toinhibit the expression of a targeted gene by generatingloss-of-function. Methods relating to the use of RNAi to silence genesin organisms including, mammals, C. elegans, Drosophila and plants, andhumans are known (see, e.g., Fire et al. (1998) Nature 391:806-811 Fire(1999) Trends Genet. 15:358-363; Sharp (2001) Genes Dev. 15:485-490;Hammond, et al. (2001) Nature Rev. Genet.2:110-1119; Tuschl (2001) Chem.Biochem. 2:239-245; Hamilton et al. (1999) Science 286:950-952; Hammondet al. (2000) Nature 404:293-296; Zamore et al. (2000) Cell 101:25-33;Bernstein et al. (2001) Nature 409: 363-366; Elbashir et al. (2001)Genes Dev. 15:188-200; Elbashir et al. (2001) Nature 411:494-498;International PCT application No. WO 01/29058; International PCTapplication No. WO 99/32619). By selecting appropriate sequences,expression of dsRNA can interfere with accumulation of endogenous mRNAencoding a targeted gene product. Regions that include at least about 21nucleotides and that are selective (i.e. whose target is unique) for thenucleic acid encoding a targeted gene product are used to prepare theRNAi.

[0171] As used herein, genetic therapy involves the transfer ofheterologous nucleic acid, such as DNA, into certain cells, targetcells, of a mammal, particularly a human, with a disorder or conditionsfor which such therapy is sought. The nucleic acid molecules areincluded in a conjugate linked via a cell surface protein cleavage site.The nucleic acid, such as DNA, is introduced into the selected targetcells in a manner such that the heterologous nucleic acid, such as DNA,is expressed and a therapeutic product encoded thereby is produced.Alternatively the heterologous nucleic acid, such as DNA, can in somemanner mediate expression of DNA that encodes the therapeutic product,or it can encode a product, such as a peptide or RNA that in some mannermediates, directly or indirectly, expression of a therapeutic product.Genetic therapy can also be used to deliver nucleic acid encoding a geneproduct that replaces a defective gene or supplements a gene productproduced by the mammal or the cell in which it is introduced. Theintroduced nucleic acid can encode a therapeutic compound, such as agrowth factor inhibitor thereof, or a tumor necrosis factor or inhibitorthereof, such as a receptor therefor, that is not normally produced inthe mammalian host or that is not produced in therapeutically effectiveamounts or at a therapeutically useful time. The heterologous nucleicacid, such as DNA, encoding the therapeutic product can be modifiedprior to introduction into the cells of the afflicted host in order toenhance or otherwise alter the product or expression thereof. Genetictherapy can also involve delivery of an inhibitor or repressor or othermodulator of gene expression, such dsRNA or antisense or other nucleicacid molecule. The conjugates herein can be used to deliver a product,such as a nucleic acid for gene therapy.

[0172] As used herein, a therapeutically effective product for genetherapy is a product that is encoded by heterologous nucleic acid,typically DNA, that, upon introduction of the nucleic acid into a host,a product is expressed that ameliorates or eliminates the symptoms,manifestations of an inherited or acquired disease or that cures thedisease. Also included are biologically active nucleic acid molecules,such as RNAi and antisense.

[0173] As used herein, a sequence complementary to at least a portion ofan RNA, with reference to antisense oligonucleotides, means a sequencehaving sufficient complementarily to be able to hybridize with the RNA,generally under moderate or high stringency conditions, forming a stableduplex; in the case of double-stranded SP antisense nucleic acids, asingle strand of the duplex DNA (or dsRNA) can thus be tested, ortriplex formation can be assayed. The ability to hybridize depends onthe degree of complementarily and the length of the antisense nucleicacid. Generally, the longer the hybridizing nucleic acid, the more basemismatches with a SP encoding RNA it can contain and still form a stableduplex (or triplex, as the case can be). One skilled in the art canascertain a tolerable degree of mismatch by use of standard proceduresto determine the melting point of the hybridized complex.

[0174] Amino acid substitutions can be made or occur in any SPs andprotease domains thereof. Amino acid substitutions include conservativesubstitutions, such as those set forth in Table 1, which do noteliminate proteolytic activity. As described herein, substitutions thatalter properties of the proteins, such as removal of cleavage sites andother such sites are also contemplated; such substitutions are generallynon-conservative, but can be readily effected by those of skill in theart.

[0175] Suitable conservative substitutions of amino acids are known tothose of skill in this art and can be made generally without alteringthe biological activity, for example enzymatic activity, of theresulting molecule. Also included within the definition, is thecatalytically active fragment of an SP, particularly a single chainprotease portion. Conservative amino acid substitutions are made, forexample, in accordance with those set forth in TABLE 1 as follows: TABLE1 Ala (A) Gly; Ser Arg (R) Lys, Orn Asn (N) Gln; His Asp (D) Glu Cys (C)Ser Gln (Q) Asn Glu (E) Asp Gly (G) Ala; Pro His (H) Asn; Gln Ile (I)Leu; Val; Nle; Met Leu (L) Ile; Val; Nle; Met Lys (K) Arg; Gln; Glu Met(M) Leu; Tyr; Ile; Nle Phe (F) Met; Leu; Tyr, Trp Ser (S) Thr Thr (T)Ser Trp (W) Tyr; Phe Tyr (Y) Trp; Phe Val (V) Ile; Leu; Nle; Met

[0176] Other substitutions are also permissible and can be determinedempirically or in accord with known conservative substitutions. Forexample, one or more amino acid residues within the sequence can besubstituted by another amino acid of a similar polarity which acts as afunctional equivalent, resulting in a silent alteration. Substitutes foran amino acid within the sequence can be selected from other members ofthe class to which the amino acid belongs. For example, the nonpolar(hydrophobic) amino acids include alanine, leucine, isoleucine, valine,proline, phenylalanine, tryptophan and methionine. The polar neutralamino acids include glycine, serine, threonine, cysteine, tyrosine,asparagine, and glutamine. The positively charged (basic) amino acidsinclude arginine, lysine and histidine. The negatively charged (acidic)amino acids include aspartic acid and glutamic acid.

[0177] As used herein, the amino acids, which occur in the various aminoacid sequences appearing herein, are identified according to theirwell-known, three-letter or one-letter abbreviations. The nucleotides,which occur in the various DNA fragments, are designated with thestandard single-letter designations used routinely in the art. Otherabbreviations, include: hR or hArg for homoarginine; hY or hTyr forhomotyrosine; Cha for cyclohexylalanine; Amf for4-aminomethylphenylalanine; DPL for 2-(4,6-dimethylpyrimidinyl)lysine;(imidazolyl)K for N′-(2-imidazolyl)lysine; Me2PO3-Y for0-dimethylphosphotyrosine; O—Me—Y for O-methyltyrosine; TIC fortetrahydro-3-isoquinoline carboxylic acid; MeL for2-keto-3-amino-5-methylhexane; DAP for 1,3-diaminopropane; TFA fortrifluoroacetic acid; AA for acetic acid.

[0178] As used herein, a splice variant refers to a variant produced bydifferential processing of a primary transcript of genomic DNA thatresults in more than one type of mRNA.

[0179] As used herein, a probe or primer based on a nucleotide sequencedisclosed herein, includes at least 10, 14, generally at least 16 or 30or 100 contiguous sequence of nucleotides.

[0180] As used herein, antisense polynucleotides refer to syntheticsequences of nucleotide bases complementary to mRNA or the sense strandof double-stranded DNA. Admixture of sense and antisense polynucleotidesunder appropriate conditions leads to the binding of the two molecules,or hybridization. When these polynucleotides bind to (hybridize with)mRNA, inhibition of protein synthesis (translation) occurs. When thesepolynucleotides bind to double-stranded DNA, inhibition of RNA synthesis(transcription) occurs. The resulting inhibition of translation and/ortranscription leads to an inhibition of the synthesis of the proteinencoded by the sense strand. Antisense nucleic acid molecules typicallycontain a sufficient number of nucleotides to specifically bind to atarget nucleic acid, generally at least 5 contiguous nucleotides, oftenat least 14 or 16 or 30 contiguous nucleotides or modified nucleotidescomplementary to the coding portion of a nucleic acid molecule thatencodes a gene of interest, for example, nucleic acid encoding a singlechain protease domain of an SP.

[0181] As used herein, an array refers to a collection of elements, suchas antibodies, containing three or more members. An addressable array isone in which the members of the array are identifiable, typically byposition on a solid phase support. Hence, in general the members of thearray are immobilized on discrete identifiable loci on the surface of asolid phase.

[0182] As used herein, antibody refers to an immunoglobulin, whethernatural or partially or wholly synthetically produced, including anyderivative thereof that retains the specific binding ability of theantibody. Hence antibody includes any protein having a binding domainthat is homologous or substantially homologous to an immunoglobulinbinding domain. Antibodies include members of any immunoglobulin claims,including IgG, IgM, IgA, IgD and IgE.

[0183] As used herein, antibody fragment refers to any derivative of anantibody that is less than full-length, retaining at least a portion ofthe full-length antibody's specific binding ability. Examples ofantibody fragments include,but are not limited to, Fab, Fab′, F(ab)₂,single-chain Fvs (scFV), FV, dsFV diabody and Fd fragments. The fragmentcan include multiple chains linked together, such as by disulfidebridges. An antibody fragment generally contains at least about 50 aminoacids and typically at least 200 amino acids.

[0184] As used herein, an Fv antibody fragment is composed of onevariable heavy domain (V_(H)) and one variable light domain linked bynoncovalent interactions.

[0185] As used herein, a dsFV refers to an Fv with an engineeredintermolecular disulfide bond, which stabilizes the V_(H)-V_(L) pair.

[0186] As used herein, an F(ab)₂ fragment is an antibody fragment thatresults from digestion of an immunoglobulin with pepsin at pH 4.0-4.5;it can be recombinantly expressed to produce the equivalent fragment.

[0187] As used herein, Fab fragments are antibody fragments that resultfrom digestion of an immunoglobulin with papain; they can berecombinantly expressed to produce the equivalent fragment.

[0188] As used herein, scFVs refer to antibody fragments that contain avariable light chain (V_(L)) and variable heavy chain (V_(H)) covalentlyconnected by a polypeptide linker in any order. The linker is of alength such that the two variable domains are bridged withoutsubstantial interference. Exemplarly linkers include, but are notlimited to, (Gly-Ser)_(n) residues, which can include ome Glu or Lysresidues dispersed throughout, for example, to increase solubility.

[0189] As used herein, humanized antibodies refer to antibodies that aremodified to include human sequences of amino acids so thatadministration to a human does not provoke an immune response. Methodsfor preparation of such antibodies are known. For example, to producesuch antibodies, the encoding nucleic acid in the hybridoma or otherprokaryotic or eukaryotic cell, such as an E. coli or a CHO cell, thatexpresses the monoclonal antibody is altered by recombinant nucleic acidtechniques to express an antibody in which the amino acid composition ofthe non-variable region is based on human antibodies. Computer programshave been designed to identify such non-variable regions.

[0190] As used herein, diabodies are dimeric scFV; diabodies typicallyhave shorter peptide linkers than scFvs, and they generally dimerize.

[0191] As used herein, production by recombinant means by usingrecombinant DNA methods means the use of the well known methods ofmolecular biology for expressing proteins encoded by cloned DNA.

[0192] As used herein, the term assessing is intended to includequantitative and qualitative determination in the sense of obtaining anabsolute value for the activity of an SP, or a domain thereof, presentin the sample, and also of obtaining an index, ratio, percentage, visualor other value indicative of the level of the activity. Assessment canbe direct or indirect and the chemical species actually detected neednot of course be the proteolysis product itself but can for example be aderivative thereof or some further substance.

[0193] As used herein, biological activity refers to the in vivoactivities of a compound or physiological responses that result upon invivo administration of a compound, composition or other mixture.Biological activity, thus, encompasses therapeutic effects andpharmaceutical activity of such compounds, compositions and mixtures.Biological activities can be observed in in vitro systems designed totest or use such activities.

[0194] As used herein, a combination refers to any association betweentwo or among more items.

[0195] As used herein, fluid refers to any composition that can flow.Fluids thus encompass compositions that are in the form of semi-solids,pastes, solutions, aqueous mixtures, gels, lotions, creams and othersuch compositions.

[0196] As used herein, an effective amount of a compound for treating aparticular disease is an amount that is sufficient to ameliorate, or insome manner reduce the symptoms associated with the disease. Such amountcan be administered as a single dosage or can be administered accordingto a regimen, whereby it is effective. The amount can cure the diseasebut, typically, is administered in order to ameliorate the symptoms ofthe disease. Repeated administration can be required to achieve thedesired amelioration of symptoms.

[0197] As used herein, equivalent, when referring to two sequences ofnucleic acids, means that the two sequences in question encode the samesequence of amino acids or equivalent proteins. When equivalent is usedin referring to two proteins or peptides, it means that the two proteinsor peptides have substantially the same amino acid sequence with aminoacid substitutions (see, e.g., Table 1, above) that do not substantiallyalter the activity or function of the protein or peptide (i.e, retain atleast about 1% of the activity). When equivalent refers to a property,the property does not need to be present to the same extent (e.g., twopeptides can exhibit different rates of the same type of enzymaticactivity), but the activities are generally substantially the same.Complementary, when referring to two nucleotide sequences, means thatthe two sequences of nucleotides are capable of hybridizing, typicallywith less than 25%, often with less than 15%, or even less than 5% orwith no mismatches between opposed nucleotides. Generally the twomolecules hybridize under conditions of high stringency.

[0198] As used herein, a method for treating or preventing disease ordisorder associated with undesired and/or uncontrolled angiogenesismeans that the diseases or the symptoms associated with the undesiredand/or uncontrolled angiogenesis are alleviated, reduced, ameliorated,prevented, placed in a state of remission, or maintained in a state ofremission. It also means that the hallmarks of pathological angiogenesisare eliminated, reduced or prevented by the treatment. Non-limitingexamples of the hallmarks of the pathological angiogenesis includeuncontrolled degradation of the basement membrane and proximalextracellular matrix of the endothelial cells, migration, division, andorganization of the endothelial cells into new functioning capillaries,and the persistence of such functioning capillaries.

[0199] As used herein, operatively linked or operationally associatedrefers to the functional relationship of DNA with regulatory andeffector sequences of nucleotides, such as promoters, enhancers,transcriptional and translational stop sites, and other signalsequences. For example, operative linkage of DNA to a promoter refers tothe physical and functional relationship between the DNA and thepromoter such that the transcription of such DNA is initiated from thepromoter by an RNA polymerase that specifically recognizes, binds to andtranscribes the DNA. In order to optimize expression and/or in vitrotranscription, it can be necessary to remove, add or alter 5′untranslated portions of the clones to eliminate extra, potentialinappropriate alternative translation initiation (i.e., start) codons orother sequences that can interfere with or reduce expression, either atthe level of transcription or translation. Alternatively, consensusribosome binding sites (see, e.g., Kozak (1991) J. Biol. Chem.266:19867-19870) can be inserted immediately 5′ of the start codon andcan enhance expression. The desirability of (or need for) suchmodification can be empirically determined.

[0200] As used herein, a promoter region or promoter element refers to asegment of DNA or RNA that controls transcription of the DNA or RNA towhich it is operatively linked. The promoter region includes specificsequences that are sufficient for RNA polymerase recognition, bindingand transcription initiation. This portion of the promoter region isreferred to as the promoter. In addition, the promoter region includessequences that modulate this recognition, binding and transcriptioninitiation activity of RNA polymerase. These sequences can be cis actingor can be responsive to trans acting factors. Promoters, depending uponthe nature of the regulation, can be constitutive or regulated.Exemplary promoters contemplated for use in prokaryotes include thebacteriophage T7 and T3 promoters.

[0201] As used herein, sample refers to anything which can contain ananalyte for which an analyte assay is desired. The sample can be abiological sample, such as a biological fluid or a biological tissue.Examples of biological fluids include urine, blood, plasma, serum,saliva, semen, stool, sputum, cerebral spinal fluid, tears, mucus,amniotic fluid or the like. Biological tissues are aggregates of cells,usually of a particular kind together with their intercellular substancethat form one of the structural materials of a human, animal, plant,bacterial, fungal or viral structure, including connective, epithelium,muscle and nerve tissues. Examples of biological tissues also includeorgans, tumors, lymph nodes, arteries and individual cell(s).

[0202] As used herein, to hybridize under conditions of a specifiedstringency is used to describe the stability of hybrids formed betweentwo single-stranded DNA fragments and refers to the conditions of ionicstrength and temperature at which such hybrids are washed, followingannealing under conditions of stringency less than or equal to that ofthe washing step. Typically high, medium and low stringency encompassthe following conditions or equivalent conditions thereto:

[0203] 1) high stringency: 0.1×SSPE or SSC, 0.1% SDS, 65° C.

[0204] 2) medium stringency: 0.2×SSPE or SSC, 0.1% SDS, 50° C.

[0205] 3) low stringency: 1.0×SSPE or SSC, 0.1% SDS, 50° C. Equivalentconditions refer to conditions that select for substantially the samepercentage of mismatch in the resulting hybrids. Additions ofingredients, such as formamide, Ficoll, and Denhardt's solution affectparameters such as the temperature under which the hybridization shouldbe conducted and the rate of the reaction. Thus, hybridization in 5×SSC,in 20% formamide at 42° C. is substantially the same as the conditionsrecited above hybridization under conditions of low stringency. Therecipes for SSPE, SSC and Denhardt's and the preparation of deionizedformamide are described, for example, in Sambrook et al. (1989)Molecular Cloning, A Laboratory Manual, Cold Spring Harbor LaboratoryPress, Chapter 8; see, Sambrook et al, vol. 3, p. B.13, see, also,numerous catalogs that describe commonly used laboratory solutions). Itis understood that equivalent stringencies can be achieved usingalternative buffers, salts and temperatures.

[0206] The terms substantially identical or similar varies with thecontext as understood by those skilled in the relevant art and generallymeans at least 40, 60, 80, 90, 95 or 98%.

[0207] As used herein, substantially identical to a product meanssufficiently similar so that the property of interest is sufficientlyunchanged so that the substantially identical product can be used inplace of the product.

[0208] As used herein, target cell refers to a cell that expresses acell surface protease.

[0209] As used herein, test substance, including compounds providedherein, refers to a chemically defined compound (e.g., organicmolecules, inorganic molecules, organic/inorganic molecules, proteins,peptides, nucleic acids, oligonucleotides, lipids, polysaccharides,saccharides, or hybrids among these molecules such as glycoproteins,etc.) or mixtures of compounds (e.g., a library of test compounds,natural extracts or culture supernatants, etc.) whose effect on orinteraction with a cell surface protein or cell surface-associatedprotein, or a domain thereof, is determined by the methods herein.

[0210] As used herein, the terms a therapeutic agent, therapeuticregimen, radioprotectant, chemotherapeutic mean conventional drugs anddrug therapies, including vaccines, which are known to those skilled inthe art. Radiotherapeutic agents are well known in the art.

[0211] As used herein, vector (or plasmid) refers to discrete elementsthat are used to introduce heterologous DNA into cells for expressionand/or replication thereof. The vectors typically remain episomal, butcan be designed to effect integration of a gene or portion thereof intoa chromosome of the genome. Also contemplated are vectors that areartificial chromosomes, such as yeast artificial chromosomes andmammalian artificial chromosomes. Selection and use of such vehicles arewell known to those of skill in the art. An expression vector includesvectors capable of expressing DNA that is operatively linked withregulatory sequences, such as promoter regions, that are capable ofeffecting expression of such DNA fragments. Thus, an expression vectorrefers to a recombinant DNA or RNA construct, such as a plasmid, aphage, recombinant virus or other vector that, upon introduction into anappropriate host cell, results in expression of the cloned DNA.Appropriate expression vectors are well known to those of skill in theart and include those that are replicable in eukaryotic cells and/orprokaryotic cells and those that remain episomal or those whichintegrate into the host cell genome.

[0212] As used herein, chemically stable means that the compound isstable enough to be formulated for pharmaceutical use. Such chemicalstability is well known to those of skill in the art and can bedetermined by well known routine methods. Whether a given compound ischemically stable enough to be formulated for pharmaceutical use dependson a number of factors including, but not limited to, the type offormulation and route of administration desired, the disease to betreated, and the method of preparing the pharmaceutical formulation.

[0213] As used herein, a “functional equivalent” of a side chain of anamino acid is a group or moiety that functions in substantially the sameway as the naturally occurring side chain to achieve substantially thesame result (e.g., a substrate for a cell surface protease). Forexample, functional equivalents of the side chain of arginine include,but are not limited to, homoarginine, guanidinoaminopropyl,guanidinoaminoethyl, (Me)₂arginine side chain, (Et)₂arginine side chain,(4-aminomethyl)phenylmethyl, 4-amidinophenylmethyl,4-guanidinophenyl-methyl, or a conformationally constrained arginineside chain analog such as:

[0214] where x is 0 or 1 (see, e.g., Webb et al. (1991) J. Org. Chem.56:3009), or a conformationally constrained arginine side chain analogsuch as:

[0215] where d is an integer from 0 to 5, or 1 to 3; and W is N or CH;or a mono- or di-substituted N-alkyl derivative of the above groups,where alkyl is, in certain embodiments, lower alkyl, such as methyl.

[0216] As used herein, pharmaceutically acceptable derivatives of acompound include salts, esters, enol ethers, enol esters, acids, bases,solvates, hydrates or prodrugs thereof. Such derivatives can be readilyprepared by those of skill in this art using known methods for suchderivatization. The compounds produced can be administered to animals orhumans without substantial toxic effects and either are pharmaceuticallyactive or are prodrugs. Pharmaceutically acceptable salts include, butare not limited to, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl andheterocyclyl esters of acidic groups, including, but not limited to,carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids,sulfinic acids and boronic acids. Pharmaceutically acceptable enolethers include, but are not limited to, derivatives of formula C═C(OR)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptableenol esters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecule, generally 1 toabout 100, typically 1 to about 10, such as 1 to about 2, 3 or 4,solvent or water molecules.

[0217] As used herein, treatment means any manner in which one or moreof the symptoms of a condition, disorder or disease are ameliorated orotherwise beneficially altered. Treatment also encompasses anypharmaceutical use of the compositions herein, such as use for treatingcancer.

[0218] As used herein, amelioration of the symptoms of a particulardisorder by administration of a particular pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

[0219] As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized or otherwise converted to thebiologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound is regenerated by metabolicprocesses. The prodrug can be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, e.g., Nogrady (1985) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York, pages388-392).

[0220] It is to be understood that the conjugates provided herein cancontain chiral centers. Such chiral centers can be of either the (R) or(S) configuration, or can be a mixture thereof. Thus, the compoundsprovided herein can be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. In the case of amino acid residues, suchresidues can be of either the L- or D-form. The configuration fornaturally occurring amino acid residues is generally L. When notspecified the residue is the L form. It is to be understood that thechiral centers of the compounds provided herein can undergoepimerization in vivo. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

[0221] The conjugates provided herein are prodrugs because they includea therapeutic agent in an inactive form that is ultimately converted toan active form at the targeted cell or tissue or in the environmentthereof. Upon exposure to targeted protease either a biologically,pharmaceutically or therapeutically active form of a compound isreleased, or, a derivative that can be further metabolized into abiologically, pharmaceutically or therapeutically active form of acompound.

[0222] As used herein, substantially pure means sufficiently homogeneousto appear free of readily detectable impurities as determined bystandard methods of analysis, such as thin layer chromatography (TLC),gel electrophoresis, high performance liquid chromatography (HPLC) andmass spectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notalter the physical and chemical properties, such as enzymatic andbiological activities, of the substance for its intended purpose.Methods for purification of the compounds to produce substantiallychemically pure compounds are known to those of skill in the art. Asubstantially chemically pure compound may, however, be a mixture ofstereoisomers. In such instances, further purification might increasethe specific activity of the compound.

[0223] As used herein, a peptidic substrate includes peptides andmolecules, such as peptide mimetics and peptides that include peptidebond surrogates.

[0224] As used herein, conventional terminology (Schecter et al. (1967)Biochem. Biophys. Res. Commun. 27:157-162) is used to refer to specificsubsites of a protease substrate: Pn . . . P3-P2-P1↓P1′-P2′-P3′ . . .Pn′. The scissile bond (i.e., the cleavage site) of a substrate isindicated by the arrow. Positions N-terminal of that bond are referredto as unprimed positions. Subsites are then assigned a number based ontheir distance from the scissile bond. Amino acids (or amino acidsurrogates) that form the scissile bond are assigned the number 1,adjacent residues the number 2, and so on, counting away from thescissile bond. Each specific subsite of the substrate, therefore, isuniquely identified by a number and the designation as primed orunprimed.

[0225] As used herein, a surrogate of a peptide bond is a divalent groupthat possesses similar steric and/or electronic characteristics to—C(O)NH—. Peptide bond surrogates include, but are not limited to,alkene isosteres (—CR═CR—), particularly (E)-alkene isosteres of formula—CH═CH—, hydroxyethylene isosteres (—CH(OH)CH₂—), enamine isosteres(—C(═CRR)NH—), aminoalcohol isosteres (—CH(OH)CH₂NH—), difluoroketoneisosteres (—C(O)CF₂—), retroinverso compounds (—NHC(O)—), divalentheterocyclyl or heteroaryl groups, and cyclopropyl isosteres such as:

[0226] As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, generally 1 to 16 carbons, andare straight or branched. Alkenyl carbon chains of from 2 to 20 carbonstypically contain 1 to 8 double bonds, and the alkenyl carbon chains of2 to 16 carbons and typically contain 1 to 5 double bonds. Alkynylcarbon chains of from 2 to 20 carbons typically contain 1 to 8 triplebonds, and the alkynyl carbon chains of 2 to 16 carbons and generallycontain 1 to 5 triple bonds. Exemplary alkyl, alkenyl and alkynyl groupsherein include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl,neopentyl, tert-pentyl and isohexyl. The alkyl, alkenyl and alkynylgroups, unless otherwise specified, optionally can be substituted, withone or more groups, generally alkyl group substituents that are the sameor different. As used herein, lower alkyl, lower alkenyl, and loweralkynyl refer to carbon chains having less than about 6 carbons. As usedherein, “alk(en)(yn)yl” refers to an alkyl group containing at least onedouble bond and at least one triple bond.

[0227] As used herein, “cycloalkyl” refers to a saturated mono- ormulti-cyclic ring system, typically 3 to 10 carbon atoms, such as, forexample, 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl refer tomono- or multicyclic ring systems that respectively include at least onedouble bond and at least one triple bond. Cycloalkenyl and cycloalkynylgroups contain, for example, 3 to 10 carbon atoms, with cycloalkenylgroups generally containing 4 to 7 carbon atoms and cycloalkynyl groupsthat contain, for example 8 to 10 carbon atoms. The ring systems of thecycloalkyl, cycloalkenyl and cycloalkynyl groups can be composed of onering or two or more rings which can be joined together in a fused,bridged or spiro-connected fashion, and optionally can be substitutedwith one or more alkyl group substituents. “Cycloalk(en)(yn)yl” refersto a cycloalkyl group containing at least one double bond and at leastone triple bond.

[0228] As used herein, “substituted alkyl,” “substituted alkenyl,”“substituted alkynyl,” “substituted cycloalkyl,” “substitutedcycloalkenyl,” and “substituted cycloalkynyl” refer to alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl groups, respectively,that are substituted with one or more substituents, in certainembodiments one to three substituents, independently selected fromalkyl, halo, haloalkyl, such as halo lower alkyl, pseudohalo, aryl,amino, dialkylamino, nitro, cyano, azido, alkylsulfinyl, alkylsulfonyl,alkylcarbonylamino, alkoxycarbonylamino, aminoimino, hydroxy, alkoxy,aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio,carboxy, alkylcarbonyl, alkoxycarbonyl, oxo and cycloalkyl.

[0229] As used herein, “aryl” refers to cyclic groups containing from 6to 19 carbon atoms. Aryl groups include, but are not limited to groups,such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl,naphthyl and substituted naphthyl. As used herein, “aryl” also refers toaryl-containing groups, including, but not limited to, aryloxy,arylthio, arylcarbonyl and arylamino groups.

[0230] As used herein, “heteroaryl” refers to a monocyclic ormulticyclic aromatic ring system, generally about 5 to about 15 memberswhere one or more, such as 1 to 3 of the atoms in the ring system is aheteroatom, that is, an element other than carbon, for example,nitrogen, oxygen and sulfur atoms. The heteroaryl group optionally canbe fused to a benzene ring. Exemplary heteroaryl groups include, forexample, furyl, imidazolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl,thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl andisoquinolinyl, with pyridyl, thienyl and quinolinyl as examples thereof.

[0231] As used herein, “heteroaryl” also refers to heteroaryl-containinggroups, including, but not limited to, heteroaryloxy, heteroarylthio,heteroarylcarbonyl and heteroarylamino.

[0232] As used herein, “heterocyclyl” refers to a monocyclic ormulticyclic non-aromatic ring system, such as systems of 3 to 10members, for exmaple 4 to 7 members or 5 to 6 members, where one ormore, such as 1 to 3 of the atoms in the ring system is a heteroatom,that is, an element other than carbon, for example, nitrogen, oxygenand/or sulfur atoms.

[0233] As used herein, “substituted aryl,” “substituted heteroaryl” and“substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclylgroups, respectively, that are substituted with one or moresubstituents, in certain embodiments one to three substituents,independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl optionally substituted with 1 or more, such as 1 to 3,substituents selected from halo, halo alkyl and alkyl, aralkyl,heteroaralkyl, alkenyl containing 1 to 2 double bonds, alkynylcontaining 1 to 2 triple bonds, alk(en)(yn)yl groups, halo, pseudohalo,cyano, hydroxy, haloalkyl and polyhaloalkyl, such as halo lower alkyl,especially trifluoromethyl, formyl, alkylcarbonyl, arylcarbonyl thatoptionally is substituted with 1 or more, generally 1 to 3, substituentsselected from halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy,alkoxycarbonyl, aryloxycarbonyl, aminoimino, alkoxycarbonylamino,aryloxycarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy,alkynyloxy, arylalkoxy, aminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl,arylaminoalkyl, amino, alkylamino, dialkyl-amino, arylamino,alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro,mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano,isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl andarylamino-sulfonyl.

[0234] As used herein, “aralkyl” refers to an alkyl group in which oneof the hydrogen atoms of the alkyl is replaced by an aryl group.

[0235] As used herein, “heteroaralkyl” refers to an alkyl group in whichone of the hydrogen atoms of the alkyl is replaced by a heteroarylgroup.

[0236] As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. isused as is generally understood by those of skill in this art. Forexample, as used herein alkyl refers to saturated carbon chains thatcontain one or more carbons; the chains can be straight or branched orinclude cyclic portions or be cyclic.

[0237] Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there can be one or more substituents present. Forexample, “haloalkyl” can include one or more of the same or differenthalogens. As another example, “C₁₋₃alkoxyphenyl” can include one or moreof the same or different alkoxy groups containing one, two or threecarbons.

[0238] As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Bror I.

[0239] As used herein, pseudohalides are compounds that behavesubstantially similar to halides. Such compounds can be used in the samemanner and treated in the same manner as halides (X⁻, in which X is ahalogen, such as Cl or Br). Pseudohalides include, but are not limitedto, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy,difluoromethoxy, dichloromethoxy and azide.

[0240] As used herein, “haloalkyl” refers to a lower alkyl radical inwhich one or more of the hydrogen atoms are replaced by halogen. Suchgroups include, but not limited to, chloromethyl, trifluoromethyl,1-chloro-2-fluoroethyl and the like.

[0241] As used herein, “haloalkoxy” refers to RO— in which R is ahaloalkyl group.

[0242] As used herein, “sulfinyl” or “thionyl” refers to —S(O)—. As usedherein, “sulfonyl” or “sulfuryl” refers to —S(O)₂—. As used herein,“sulfo” refers to —S(O)₂O—.

[0243] As used herein, “carboxy” refers to a divalent radical, —C(O)O—.

[0244] As used herein, “aminocarbonyl” refers to —C(O)NH₂.

[0245] As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in whichR is hydrogen or alkyl, such as, for example, lower alkyl.

[0246] As used herein “dialkylaminocarbonyl” as used herein refers to—C(O)NR′R in which R′ and R are independently selected from hydrogen oralkyl, such as, for example, lower alkyl; “carboxamide” refers to groupsof formula —NR′COR.

[0247] As used herein, “diarylaminocarbonyl” refers to —C(O)NRR′ inwhich R and R′ are independently selected from aryl, such as lower aryl,for example, phenyl.

[0248] As used herein, “aralkylaminocarbonyl” refers to —C(O)NRR′ inwhich one of R and R′ is aryl, such as, lower aryl, for example, phenyl,and the other of R and R′ is alkyl, such as, for example, lower alkyl.

[0249] As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which Ris aryl, such as lower aryl, for example, phenyl.

[0250] As used herein, “hydroxycarbonyl” refers to —COOH.

[0251] As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R isalkyl, such as lower alkyl.

[0252] As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R isaryl, such lower aryl, for example phenyl.

[0253] As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, inwhich R is alkyl, such as, for example, lower alkyl.

[0254] As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, inwhich R is aryl, such lower aryl, for example, phenyl.

[0255] As used herein, “alkylene” refers to a straight, branched orcyclic, such as, for example, straight or branched, divalent aliphatichydrocarbon group, for example, having from 1 to about 20 carbon atomssuch as 1 to 12 carbons, and for exmaple, is lower alkylene. Thereoptionally can be inserted along the alkylene group one or more oxygen,sulphur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl as previously described. Exemplaryalkylene groups include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—(CH₂)₃—), cyclohexylene (—C₆H₁₀—), methylenedioxy(—O—CH₂—O—) and ethylenedioxy (—O—(CH₂)₂—O—). The term “lower alkylene”refers to alkylene groups having 1 to 6 carbons. Exemplary alkylenegroups are lower alkylene, such as, for example, alkylene of 1 to 3carbon atoms.

[0256] As used herein, “alkenylene” refers to a straight, branched orcyclic, typically straight or branched, divalent aliphatic hydrocarbongroup, such as, for example, having from 2 to about 20 carbon atoms andat least one double bond, generally 1 to 12 carbons, and is for example,lower alkenylene. There optionally can be inserted along the alkenylenegroup one or more oxygen, sulphur or substituted or unsubstitutednitrogen atoms, where the nitrogen substituent is alkyl as previouslydescribed. Exemplary alkenylene groups include —CH═CH—CH═CH— and—CH═CH═CH₂—. The term “lower alkenylene” refers to alkenylene groupshaving 2 to 6 carbons. Examplary alkenylene groups are lower alkenylene,such as, for example, alkenylene of 3 to 4 carbon atoms.

[0257] As used herein, “alkynylene” refers to a straight, branched orcyclic, generally straight or branched, divalent aliphatic hydrocarbongroup, such those having from 2 to about 20 carbon atoms and at leastone triple bond, generally 1 to 12 carbons, such as, for example, loweralkynylene. There optionally can be inserted along the alkynylene groupone or more oxygen, sulphur or substituted or unsubstituted nitrogenatoms, where the nitrogen substituent is alkyl as previously described.Exemplary alkynylene groups include —C≡C—C≡C—, —C≡C— and —C≡C—CH₂—. Theterm “lower alkynylene” refers to alkynylene groups having 2 to 6carbons. Exemplary alkynylene groups are lower alkynylene, such as, forexample, alkynylene of 3 to 4 carbon atoms.

[0258] As used herein, “alk(en)(yn)ylene” refers to a straight, branchedor cyclic, generally straight or branched, divalent aliphatichydrocarbon group, having, for example, from 2 to about 20 carbon atomsand at least one triple bond, and at least one double bond; typically 1to 12 carbons, such as, for example, lower alk(en)(yn)ylene. Thereoptionally can be inserted along the alkynylene group one or moreoxygen, sulphur or substituted or unsubstituted nitrogen atoms, wherethe nitrogen substituent is alkyl as previously described. Exemplaryalk(en)(yn)ylene groups include —C═C—(CH₂)_(n)—C≡C—, where n is 1 or 2.The term “lower alk(en)(yn)ylene” refers to alk(en)(yn)ylene groupshaving up to 6 carbons. Exemplary alk(en)(yn)ylene groups are loweralk(en)(yn)ylene, such as, for example, alk(en)(yn)ylene of 4 carbonatoms.

[0259] As used herein, “cycloalkylene” refers to a divalent saturatedmono- or multicyclic ring system, generally 3 to 10 carbon atoms, suchas 3 to 6 carbon atoms; cycloalkenylene and cycloalkynylene refer todivalent mono- or multicyclic ring systems that respectively include atleast one double bond and at least one triple bond. Cycloalkenylene andcycloalkynylene groups can contain 3 to 10 carbon atoms, with, forexample, cycloalkenylene groups containing 4 to 7 carbon atoms andcycloalkynylene groups containing 8 to 10 carbon atoms. The ring systemsof the cycloalkylene, cycloalkenylene and cycloalkynylene groups can becomposed of one ring or two or more rings that can be joined together ina fused, bridged or spiro-connected fashion. “Cycloalk(en)(yn)ylene”refers to a cycloalkylene group containing at least one double bond andat least one triple bond.

[0260] As used herein, “substituted alkylene,” “substituted alkenylene,”“substituted alkynylene,” “substituted cycloalkylene,” “substitutedcycloalkenylene,” and “substitued cycloalkynylene” refer to alkylene,alkenylene, alkynylene, cycloalkylene, cycloalkenylene andcycloalkynylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three substituents,independently selected from halo, haloalkyl, such as, for example, halolower alkyl, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio,arylthio, aralkyloxy, aralkylthio, carboxy alkoxycarbonyl, oxo andcycloalkyl.

[0261] As used herein, “arylene” refers to a monocyclic or polycyclic,such as monocyclic, divalent aromatic group, for example, having from 5to about 20 carbon atoms and at least one aromatic ring, such as 5 to 12carbons, and, is, for example, lower arylene. There optionally can beinserted around the arylene group one or more oxygen, sulphur orsubstituted or unsubstituted nitrogen atoms, where the nitrogensubstituent is alkyl as previously described. Exemplary arylene groupsinclude 1,2-, 1,3- and 1,4-phenylene. The term “lower arylene” refers toarylene groups having 5 or 6 carbons. Exemplary arylene groups are lowerarylene.

[0262] As used herein, “heteroarylene” refers to a divalent monocyclicor multicyclic aromatic ring system, such as of about 5 to about 15members where one or more, typically, for example, 1 to 3 of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, for example, nitrogen, oxygen and/or sulfur atom(s).

[0263] As used herein, “heterocyclylene” refers to a divalent monocyclicor multicyclic non-aromatic ring system, generally of 3 to 10 members,such as, for example, 4 to 7 members or 5 to 6 members, where one ormore, such as, for example, 1 to 3 of the atoms in the ring system is aheteroatom, that is, an element other than carbon, for example,nitrogen, oxygen and/or sulfur atom(s).

[0264] As used herein, “substituted arylene,” “substitutedheteroarylene” and “substituted heterocyclylene” refer to arylene,heteroarylene and heterocyclylene groups, respectively, that aresubstituted with one or more substituents, in certain embodiments one tothree substituents, independently selected from alkyl, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl optionally substituted with 1 or more,such as 1 to 3, substituents selected from halo, halo alkyl and alkyl,aralkyl, heteroaralkyl, alkenyl containing 1 to 2 double bonds, alkynylcontaining 1 to 2 triple bonds, alk(en)(yn)yl groups, halo, pseudohalo,cyano, hydroxy, haloalkyl and polyhaloalkyl, such as, halo lower alkyl,for example trifluoromethyl, formyl, alkylcarbonyl, arylcarbonyl thatoptionally is substituted with 1 or more, such as 1 to 3, substituentsselected from, for example, halo, halo alkyl and alkyl,heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy,aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino,alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino,arylcarbonylamino, azido, nitro, mercapto, alkylthio, arylthio,perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl.

[0265] As used herein, “alkylidene” refers to a divalent group, such as═CR′R″, which is attached to one atom of another group, forming a doublebond. Exemplary alkylidene groups are methylidene (═CH₂) and ethylidene(═CHCH₃). As used herein, “aralkylidene” refers to an alkylidene groupin which either R′ or R″ is an aryl group. “Cycloalkylidene” groups arethose where R′ and R″ are linked to form a carbocyclic ring.“Heterocyclylidene” groups are those where at least one of R′ and R″contain a heteroatom in the chain, and R′ and R″ are linked to form aheterocyclic ring.

[0266] As used herein, “amido” refers to the divalent group —C(O)NH—.“Thioamido” refers to the divalent group —C(S)NH—. “Oxyamido” refers tothe divalent group —OC(O)NH—. “Thiaamido” refers to the divalent group—SC(O)NH—. “Dithiaamido” refers to the divalent group —SC(S)NH—.“Ureido” refers to the divalent group —HNC(O)NH—. “Thioureido” refers tothe divalent group —HNC(S)NH—.

[0267] As used herein, “semicarbazide” refers to —NHC(O)NHNH—.“Carbazate” refers to the divalent group —OC(O)NHNH—. “Isothiocarbazate”refers to the divalent group —SC(O)NHNH—. “Thiocarbazate” refers to thedivalent group —OC(S)NHNH—. “Sulfonylhydrazide” refers to the group—SO₂NHNH—. “Hydrazide” refers to the divalent group —C(O)NHNH—. “Azo”refers to the divalent group —N═N—. “Hydrazinyl” refers to the divalentgroup —NH—NH—.

[0268] As used herein, the term “amino acid” refers to α-amino acidswhich are racemic, or of either the D- or L-configuration. Thedesignation “d” preceding an amino acid designation (e.g., dAla, dSer,dVal, etc.) refers to the D-isomer of the amino acid. The designation“dI” preceding an amino acid designation (e.g., dIPip) refers to amixture of the L- and D-isomers of the amino acid.

[0269] As used herein, when any particular group, such as phenyl orpyridyl, is specified, this means that the group is unsubstituted or issubstituted. Exemplary substituents where not specified are halo, halolower alkyl, and lower alkyl.

[0270] As used herein, the abbreviations for any protective groups,amino acids and other compounds, are, unless indicated otherwise, inaccord with their common usage, recognized abbreviations, or theIUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

[0271] As used herein, HHT and CHT refer to hexahydrotyrosyl (also knownas cyclohexyltyrosyl or p-hydroxycyclohexylalanyl), CHA iscyclohexylalanyl, Pyr and pyroGlu refer to pyroglutamic acid, Pip ispipecolinic acid, Sar is sarcosine, nLeu and Nle are norleucine, nVal isnorvaline, Aib is 2-aminoisobutyric acid, Quat is(R)-Glu(α-(3-amidinobenzyl)), and Abu and But are 2-aminobutyric acid.

[0272] As used herein, PEG represents a polyethylene glycol containingsubstituent having the designated number of ethyleneoxy subunits. Thus,the term PEG(2) represents:

[0273] and the term PEG(6) represents:

[0274] When R¹ and R² are combined to form —(CH₂)_(h)—, the cyclicmoieties and heteroatom-containing cyclic moieties so defined include,but are not limited to:

[0275] As used herein, the term “hydroxylated” represents substitutionon a substitutable carbon of the ring system being so described by ahydroxyl moiety. As used herein, the term “polyhydroxylated” representssubstitution on two or more substitutable carbons of the ring systembeing so described by 2, 3 or 4 hydroxyl moieties.

[0276] As used herein, the term “(d)(2,3-dihydroxypropionyl)” representsthe following structure:

[0277] As used herein, the term “(2R,3S)-2,3,4-trihydroxybutanoyl”represents the following structure:

[0278] As used herein, the term “quinyl” represents the followingstructure:

[0279] or a diastereomer thereof.

[0280] As used herein, the term “gulonyl” represents the followingstructure:

[0281] or a diastereomer thereof.

[0282] As used herein, the term “cotininyl” represents the followingstructure:

[0283] or a diastereomer thereof.

[0284] As used herein, the term “gallyl” represents the followingstructure:

[0285] As used herein, the term “4-ethoxysquaryl” represents thefollowing structure:

[0286] As used herein, 1-methylHis or (1Me)H refers to the structure:

[0287] As used herein, 3-methylHis or (3Me)H refers to the structure:

[0288] As used herein, Quat² refers to:

[0289] Quat³ refers to:

[0290] Quat⁴ refers to:

[0291] and

[0292] Quat⁵ refers to:

[0293] Other abbreviations as used herein are as follows: AbbreviationRefers to Aib 2-aminoisobutyryl 4,4-dimethylThr2-amino-3-hydroxy-4-methylpentanoyl Met(O₂) methioninyl-S,S-dioxideSer(OMe) the O-methyl ether of serinyl, also known as2-amino-3-methoxypropanoyl hSer homoserinyl, also known as 2-amino-4-hydroxybutanoyl (hS)Gly N-(2-hydroxyethyl)glycyl N,N-dimethylGlyN,N-dimethylglycyl β-Ala 3-aminopropanoyl Cys(Me) S-methylcysteinylt-butylGly 2-amino-3,3-dimethylbutanoyl F(Gn) 4-guanidinyiphenylalanylhCHA homocyclohexylalanyl, or 2-amino-4- cyclohexylbutanoyl hexylGly2-aminooctanoyl allylGly 2-amino-4-pentenoyl Inact. inactive NT nottested MeOEtCO 3-methoxypropanoyl 3,4-MethyldioxyPhAc3,4-methylenedioxyphenylacetyl L-3-PhLactylL-2-hydroxy-3-phenylpropanoyl MeOEtOCO 2-methoxyethoxycarbonyl MeOCOmethoxycarbonyl MeO(EtO)2Ac 2-(2-methoxyethoxy)ethoxyacetyl 2-PyridylAc2-pyridylacetyl PhOAc phenoxyacetyl MeOAc methoxyacetyl PhAcphenylacetyl MeOEtOAc 2-methoxyethoxyacetyl HOOCButa glutaryl Zbenzyloxycarbonyl EtOCO ethoxycarbonyl βA beta-alanyl or3-aminopropanoyl NapAc 1-naphthylacetyl iBoc isobutoxycarbonyl HOAchydroxyacetyl MeSucc 3-methoxycarbonylpropanoyl Succ succinyl HCO formyl4-(guan)Phg 4-guanidinylphenylglycyl Dox doxorubicin Tax taxol dA(Chx)or dCha d-cyclohexylalanyl dhF d-homophenylalanyl P(OH) 4-hydroxyprolyl

B. Protease Targets

[0294] The conjugates herein are designed to target proteases that arelocated on cell surfaces, particularly tumor cells and cells involved intumorigenic processes and angiogenesis and other proliferativeprocesses. The conjugates, described in detail below, contain a peptidicsubstrate for a selected targeted cell surface protease linked, eitherdirectly or via a linker, to a therapeutic agent, typically a cytotoxicagent, which is substantially inactive when in the conjugate. Thetherapeutic agent is released in a form that is active or that can beactivated in the vicinity of the targeted cell or tissue to which it isdelivered. As a result, active therapeutic agent accumulates at thetargeted cells or tissue or in the targeted cells.

[0295] The targeted protease is selected by identifying a protease thatis located on a cell or tissue (or associated therewith) that isinvolved in the disease process or serendipitously present in the localeof cells or tissues involved in the disease or disease process, and,generally, is not located at all or present or active at lower levels,generally substantially lower levels, or exhibits altered activity orspecificity, on many, if not all, other cells or tissues. The varietyand numbers of non-targeted cells or tissues that expresss the activeprotease varies for particular proteases and diseases intended fortreatment. Those of skill in the art will select a target based upon thedisease, targeted agents and tolerable or acceptable levels ofside-effects. The goal is to achieve enhanced therapeutic index comparedwith administration of the targeted agent by itself.

[0296] The targeted protease may or may not be involved in the diseaseprocess and its expression can be serendiptous; for purposes herein itsparticular role or lack thereof is not important; it is the fact that itis active in the locale of targeted tissues or cells that is important.For example, many of the cell surface proteases of interest herein areexpressed or active on tumor cells or cells involved in the tumorigenicprocesses. Any method known to one of skill in the art for determiningor detecting a tissue or cell expression profile can be used. Forexample, RNA blots composed of RNA from numerous tissues (e.g., amultiple tissue expression (MTE) array available from CLONTECH, PaloAlto, Calif.), can be screened with probes based upon the nucleic acidsequence of the protease of interest to identify cells that express theprotease. Northern analysis of the blots to test for expression also canbe used.

[0297] Included among the targeted proteases are those designated typeII membrane-bound serine proteases (MTSPs; see, e.g., U.S. applicationSer. No. 09/776,191, filed Feb. 2, 2001 and International PCTapplication No. PCT/US01/03471 published as International PCTapplication No. WO 01/57194; see International PCT application No.PCT/US02/07903; see, also U.S. provisional application Serial Nos.60/275,592, 60/278,166, 60/279,228, 60/291,001, 60/291,501 60/316,818,60/302,939, 60/316,818, 60/328,529, 60/328,530, 60/332,015, 60/328,939,and provisional application, filed on May 20, 2002 under attorney docketno. 24745-P1624; U.S. application Ser. Nos. 10/099,700, 10/104,271,10/112,221, application filed on May 14, 2002 under attorney docket no.24745-1616) and those found on endothelial cells designatedendotheliases (see, U.S. application Ser. No. 09/717,473, filed Nov. 20,2000, and International PCT application No. PCT/US00/31803 published asInternational PCT application No. WO 01/36604); see, also SEQ ID Nos.3-26, 269-270 and 272-276.

[0298] Also contemplated are proteases that are located at the cellsurface by virtue of a specific interaction with a cell surface protein.Urokinase plasminogen activator (u-PA) bound to urokinase plasminogenactivator receptor (u-PAR) is exemplary of such proteases. Nucleic acidsequence information and expression profiles of exemplary MTSPs andendotheliases are as follows (see, also EXAMPLE 6).

[0299] 1. MTSPs

[0300] Cell surface proteolysis is a mechanism for the generation ofbiologically active proteins that mediate a variety of cellularfunctions. These membrane-anchored proteins, include a disintegrin-likeand metalloproteinase (ADAM) and membrane-type matrix metalloproteinase(MT-MMP). In addition to the MMPs, serine proteases have been implicatedin neoplastic disease progression. Most serine proteases, which areeither secreted enzymes or are sequestered in cytoplasmic storageorganelles, have roles in blood coagulation, wound healing, digestion,immune responses and tumor invasion and metastasis.

[0301] Transmembrane serine proteases (MTSPs) appear to be involved inthe etiology and pathogenesis of tumors. These enzymes are expressed incertain cancerous and tumor cells and in other cells associated withother proliferative disorders and other disease states, such as ininflammatory cells and and can be tissue or organ-specific. In mammals,more than 20 members of the family are known (see, Hooper et al. (2001)J. Biol. Chem. 276:857-860, see, also U.S. application Ser. No.09/776,191, filed Feb. 2, 2001 and International PCT application No.PCT/US01/03471; see, also U.S. provisional application Serial Nos.60/275,592 and 60/278,166; and see SEQ ID Nos. 1-37). These includecorin (accession nos. AF133845 and AB013874; see, Yan et al. (1999) J.Biol. Chem. 274:14926-14938; Tomia et al. (1998) J. Biochem.124:784-789; Uan et al. (2000) Proc. Natl. Acad. Sci. U.S.A.97:8525-8529); enterpeptidase (also designated enterokinase; accessionno. U09860 for the human protein; see, Kitamoto et al. (1995) Biochem.27: 4562-4568; Yahagi et al. (1996) Biochem. Biophys. Res. Commun.219:806-812; Kitamoto et al. (1994) Proc. Natl. Acad. Sci. U.S.A.91:7588-7592; Matsushima et al. (1994) J. Biol. Chem. 269:19976-19982;);human airway trypsin-like protease (HAT; accession no. AB002134; seeYamaoka et al. J. Biol. Chem. 273:11894-11901); MTSP1 (also calledTADG-15 and matriptase, see SEQ ID Nos. 1 and 2; accession nos.AF133086/AF118224, AF04280022; Takeuchi et al. (1999) Proc. Natl. Acad.Sci. U.S.A. 96:11054-1161; Lin et al. (1999) J. Biol. Chem.274:18231-18236; Takeuchi et al. (2000) J. Biol. Chem. 275:26333-26342;and Kim et al. (1999) Immunogenetics 49:420-429); hepsin (see, accessionnos. M18930, AF030065, X70900; Leytus et al. (1988) Biochem. 27:11895-11901; Vu et al. (1997) J. Biol. Chem. 272:31315-31320; and Farleyet al. (1993) Biochem. Biophys. Acta 1173:350-352; and see, U.S. Pat.No. 5,972,616); TMPRS2 (see, Accession Nos. U75329 and AF113596;Paoloni-Giacobino et al. (1997) Genomics 44:309-320; and Jacquinet etal. (2000) FEBS Lett. 468: 93-100); and TMPRSS4 (see, Accession No. NM016425; Wallrapp et al. (2000) Cancer 60:2602-2606). Also known MTSP3,MTSP4, MTSP6, MTSP7, MTSP9, MTSP10, MTSP12, MTSP20, MTSP22 and MTSP25(see, SEQ ID NOs. 3-26, 269-270 and 272-276; see, also U.S. applicationSer. No. 09/776,191, filed Feb. 2, 2001 and International PCTapplication No. PCT/US01/03471 published as International PCTapplication No. WO 01/57194; see International PCT application No.PCT/US02/07903; see, also U.S. provisional application Serial Nos.60/275,592, 60/278,166, 60/279,228, 60/291,001, 60/291,50160/316,818,60/302,939, 60/316,818, 60/328,529, 60/328,530, 60/332,015, 60/328,939,and provisional application, filed on May 20 2002, under attorney docketno. 24745-P1624; U.S. application Ser. Nos. 10/099,700, 10/104,271,10/112,221, application filed on May 14, 2002 under attorney docket no.24745-1616)).

[0302] Serine proteases, including transmembrane serine proteases, havebeen implicated in processes involved in neoplastic development andprogression. While the precise role of these proteases has not beenelaborated, serine proteases and inhibitors thereof are involved in thecontrol of many intra- and extracellular physiological processes,including degradative actions in cancer cell invasion, metastaticspread, and neovascularization of tumors, that are involved in tumorprogression. It is believed that proteases are involved in thedegradation of extracellular matrix (ECM) and contribute to tissueremodeling, and are necessary for cancer invasion and metastasis. Theactivity and/or expression of some proteases have been shown tocorrelate with tumor progression and development, and also are shown tobe active in specific cell types.

[0303] For example, a membrane-type serine protease MTSP1 (also calledmatriptase; see SEQ ID Nos. 1 and 2 from U.S. Pat. No. 5,972,616; andGenBank Accession No. AF118224; (1999) J. Biol. Chem. 274:18231-18236;U.S. Pat. No. 5,792,616; see, also Takeuchi (1999) Proc. Natl. Acad.Sci. U.S.A. 96:11054-1161) that is expressed in epithelial cancer andnormal tissue (Takeucuhi et al. (1999) Proc. Natl. Acad. Sci. USA96:11054-61) has been identified. It has been proposed that it plays arole in the metastasis of breast cancer. Its primary cleavagespecificity is Arg-Lys residues. Matriptase also is expressed in avariety of epithelial tissues with high levels of activity and/orexpression in the human gastrointestinal tract and the prostate.

[0304] Hepsin, a cell surface serine protease identified in hepatomacells, is overexpressed in ovarian cancer (Tanimoto et al. (1997) CancerRes., 57:2884-7). The hepsin transcript appears to be abundant incarcinoma tissue and is almost never expressed in normal adult tissue,including normal ovary. It has been suggested that hepsin is frequentlyoverexpressed in ovarian tumors and therefore can be a candidateprotease in the invasive process and growth capacity of ovarian tumorcells.

[0305] A serine protease-like gene, designated normal epithelialcell-specific 1 (NES1) (Liu et al. (1996) Cancer Res. 56:3371-9) hasbeen identified. Although expression of the NES1 mRNA is observed in allnormal and immortalized nontumorigenic epithelial cell lines, themajority of human breast cancer cell lines show a drastic reduction or acomplete lack of its expression. The structural similarity of NES1 topolypeptides known to regulate growth factor activity and a negativecorrelation of NES1 expression with breast oncogenesis suggest a director indirect role for this protease-like gene product in the suppressionof tumorigenesis.

[0306] Exemplary MTSPs

[0307] Each MTSP has a characteristic tissue expression profile; theMTSPs in particular, although not exclusively expressed or activated intumors, exhibit characteristic tumor tissue expression or activationprofiles. In some instances, MTSPs can have different activity in atumor cell from a non-tumor cell by virtue of a change in a substrate orcofactor therefor or other factor that would alter functional activityof the MTSP. Hence each can serve as a diagnostic marker for particulartumors, by virtue of a level of activity and/or expression or functionin a subject (i.e. a mammal, particularly a human) with neoplasticdisease, compared to a subject or subjects that do not have theneoplastic disease. In addition, detection of activity (and/orexpression) in a particular tissue can be indicative of neoplasticdisease. Also, by virtue of the activity and/or expression profiles ofeach, they can serve as therapeutic targets, such as by administrationof modulators of the activity thereof, or, as by administration of aprodrug specifically activated by one of the MTSPs. Each or any of theMTSPs can exhibit activity or expression levels or substratespecificities that differ in tumor cells from the levels in normalcells. Such tumor cells include, but are not limited to, colon, lung,prostate, breast, esophagous, pancreas, cervic, uterus, endometrium, andother solid tumors and in blood and lymphatic tumors. Hence, conjugatesprovided herein can be designed by selection of substrate specificityfor treatment of any of such tumors and neoplastic conditions.

[0308] Tissue Expression Profiles

[0309] The following are exemplary tissue and gene (see also, EXAMPLE 8)profiles of some exemplary MTSPs. These profiles are not intended todefine the full scope of expression or activation of these MTPSs, butdemonstrate that MTSPs are expressed in tumors, and, hence thereexpression or activation or substrate specificity on the surface oftumor cells can be exploited in the methods herein and conjugates,designed in accord with the methods herein and as exemplified herein,that are cleaved by one or more of these MTSPs can be prepared andemployed for treatment of neoplastic or other diseases or conditions orto target to cells that express these proteins on there surfaces.

[0310] MTSP1 (Matriptase)

[0311] MTSP1 (also called matriptase) is a trypsin-like serine proteasewith broad spectrum cleavage activity and two potential regulatorymodules. It was named “matriptase” based on its ability to degrade theextra-cellular matrix and its trypsin-like activity. When isolated frombreast cancer cells (or T-47D cell conditioned medium), MTSP1 has beenreported to be primarily in an uncomplexed form. MTSP1 has been isolatedfrom human milk; when isolated from human milk, it was reported to be inone of two complexed forms, 95 kDa (the predominant form) and 110 kDa;uncomplexed MTSP1 was not detected (Liu, et al. (1999) J. Biol. Chem.274:18237-18242). It has been proposed that MTSP1 exists as anuncomplexed protease when in its active state. In breast milk, it hasbeen reported to exist in complex with a fragment of hepatocyte growthfactor inhibitor-1 (HAI-1), a Kunitz-type serine protease inhibitorhaving activity against trypsin-like serine proteases.

[0312] Nucleic acids encoding the protein designed matriptase werecloned from T-47D human breast cancer cell-conditioned medium (Lin etal. (1999) J. Biol. Chem. 274:18231-18236). Upon analysis of the cDNA,it was determined that the full length protease has 683 amino acids andcontains three main structural regions: a serine protease domain nearthe carboxyl-terminal region, four tandem low-density lipoproteinreceptor domains, and two tandem complement subcomponents C1r and C1s(see SEQ ID No. 1). Studies to identify additional serine proteases madeby cancer cells were done using PC-3 cells. A serine protease termed“MT-SP1” (MTSP1) by the authors, reported to be a transmembrane proteasewas cloned (Takeuchi et al. (1999) Proc. Natl. Acad. Sci. U.S.A.96:11054-11061). It was subsequently found that originally identifiedmatriptase sequence is included in the translated sequence of the cDNAthat encodes MTSP1. The nucleic acid encoding the protein originallydesignated matriptase is a partial MTSP1 clone that lacks 516 of thecoding nucleotides (Takeuchi, et al., J. Biol. Chem 275:26333-26342(2000).) Since the reported matriptase encoding cDNA sequence encoded apossible initiating methionine, it was proposed that alternativesplicing could yield a protein lacking the N-terminal region of MTSP1.Hence, matriptase herein is a variant form of MTSP1.

[0313] MTSP1 demonstrates trypsin-like protease activity and is a TypeII transmembrane protein with an extracellular protease domain. Studiesof substrate specificity of MTSP1 reveal that protease-activatedreceptor 2 (PAR2), pro-hepatacyte growth factor (pro-HGF) andsingle-chain urokinase-type plasminogen activator (sc-uPA) aremacromolecular substrates of MTSP1. PAR2 functions in inflammation,cytoprotection and/or cell adhesion, while sc-uPa functions in tumorcell invasion and metastasis. HGF serves a growth and pro-angiogenicfactor.

[0314] An exemplary nucleotide sequence encoding a human MTSP1 is setforth in SEQ ID Nos 1 and 2. As previously noted SEQ ID No. 1 sets foran MTSP1-encoding nucleic acid sequence. This sequence is the longerversion and includes the protease domain, which is common to bothvariants.

[0315] MTSP1 is expressed in breast, prostate and colorectal tumors.Hence conjugates with substrates therefor can be used for treatment ofsuch tumors.

[0316] MTSP3

[0317] The MTSP3 transcript was detected in lung carcinoma (LX-1), colonadenocarcinoma (CX-1), colon adenocarcinoma (GI-112) and ovariancarcinoma (GI-102). No apparent signal was detected in another form oflung carcinoma (GI-117), breast carcinoma (GI-101), pancreaticadenocarcinoma (GI-103) and prostatic adenocarcinoma (PC3).

[0318] MTSP4

[0319] The MTSP4 transcript, a DNA fragment encoding part of the LDLreceptor domain and the protease domain was used to probe an RNA blotcomposed of 76 different human tissues (catalog number 7775-1; humanmultiple tissue expression (MTE) array; CLONTECH). As in the northernanalysis of gel blot, a very strong signal was observed in the liver.Signals in other tissues were observed in (decreasing signal level):fetal liver>heart=kidney=adrenal gland=testis=fetal heart andkidney=skeletal muscle=bladder=placenta>brain=spinalcord=colon=stomach=spleen=lymph node=bonemarrow=trachea=uterus=pancreas=salivary gland=mammary gland=lung. MTSP4also is expressed less abundantly in several tumor cell lines includingHeLa S3=leukemia K-562=Burkitt's lymphomas (Raji and Daudi)=colorectaladenocarcinoma (SW480)>lung carcinoma (A549)=leukemia MOLT-4=leukemiaHL-60. PCR of the MTSP4 transcript from cDNA libraries made from severalhuman primary tumors xenografted in nude mice (human tumor multipletissue cDNA panel, catalog number K1522-1, CLONTECH) was performed usingMTSP4-specific primers. The MTSP4 transcript was detected in breastcarcinoma (GI-101), lung carcinoma (LX-1), colon adenocarcinoma (GI-112)and pancreatic adenocarcinoma (GI-103). No apparent signal was detectedin another form of lung carcinoma (GI-117), colon adenocarcinoma (CX-1),ovarian carcinoma (GI-102). and prostatic adenocarcinoma (PC3). TheMTSP4 transcript was also detected in LNCaP and PC-3 prostate cancercell lines as well as in HT-1080 human fibrosarcoma cell line.

[0320] MTSP6

[0321] MTSP6 is expressed at high levels in the colon. It also isexpressd in the, stomach, trachea, mammary gland, thyroid gland,salivary gland, pituitary gland and pancreas. It is expressed at lowerlevels in other tissues (see EXAMPLE 6).

[0322] MTSP6 also is expressed in several tumor cell lines includingHeLa S3>colorectal adenocarcinoma (SW480)>leukemia MOLT-4>leukemiaK-562. In mouse xenograft models, the MTSP6 transcript was stronglydetected in lung carcinoma (LX-1), moderately detected in pancreaticadenocarcinoma (GI-103), weakly detected in ovarian carcinoma (GI-102);and weakly detected in colon adenocarcinoma (GI-112 and CX-1), breastcarcinoma (GI-101), lung carcinoma (GI-117) and prostatic adenocarcinoma(PC3). The MTSP6 transcript was also detected in breast cancer cell lineMDA-MB-231, prostate cancer cell line PC-3, but not in HT-1080 humanfibrosarcoma cell line. MTSP6 also is expressed in mammary glandcarcinoma cDNA (Clontech). MTSP6 also is over expressed in ovarian tumorcells.

[0323] MTSP7

[0324] The MTSP7 transcript was detected in lung carcinoma (A549 cellline), leukemia (K-562 cell line) and cervical carcinoma (HeLaS3 cellline). MTSP7 is believed to be expressed in lung, colon, prostate,breast, cervical and other tumors.

[0325] MTSP9

[0326] MTSP9 is, for example, expressed in esophageal tumor tissues, inlung carcinoma, in colorectal carcinoma, lymphoma, a cervical carcinoma(HeLaS3) and leukemia cell lines as well as in certain normal cells andtissues. MTSP9 also can be a marker for breast, prostate, cervical andcolon cancer.

[0327] MTSP9 is highly expressed in the esophagus and expressed at a lowlevel in many other tissues. The MTSP9 transcript is found in kidney(adult and fetal), spleen (adult and fetal), placenta, liver (adult andfetal), thymus, peripheral blood leukocyte, lung (adult and fetal),pancreas, lymph node, bone marrow, trachea, uterus, prostate, testes,ovary and the gland organs (mammary, adrenal, thyroid, pituitary andsalivary). MTSP9 also is expressed in esophagus tumor tissues, in a lungcarcinoma and, at a lower level, in a colorectal carcinoma, lymphoma, acervical carcinoma (HeLaS3) and leukemia cell lines.

[0328] MTSP10

[0329] MTSP10, for example, is expressed in esophageal tumor tissues, inlung carcinoma, prostate cancers, pancreatic and breast cancers and incell lines as well as in certain normal cells and tissues (see e.g.,EXAMPLES for tissue-specific expression profile). The level of activatedMTSP10 can be diagnostic of prostate, uterine, lung esophagus, or coloncancer or leukemia or other cancer. The expression and/or activation ofMTSP10 on or in the vicinity of a cell or in a bodily fluid in a subjectcan be a marker for breast, prostate, lung, colon, esophageal and othercancers.

[0330] MTSP10 transcript was detected in pancreas, lung and kidney.MTSP10 transcript was also detected in small intestine Marathon-ReadycDNA (Clontech). The MTSP10 transcript was detected in breast carcinoma(GI-101), lung carcinoma (LX-1 and GI-117), ovarian carcinoma (GI-102),and pancreatic adenocarcinoma (GI-103). The MTSP10 transcript was weaklydetected in prostatic adenocarcinoma (PC3). The MTSP10 transcript wasalso detected in CWR22R prostate tumor grown in nude mice. No apparentsignal was detected in two forms of colon adenocarcinomas (GI-112 andCX-1).

[0331] MTSP12

[0332] MTSP12 transcript was detected in pancreas, lung and kidney.MTSP12 transcript was also detected in small intestine Marathon-ReadycDNA (Clontech). The MTSP12 transcript was detected in breast carcinoma(GI-101), lung carcinoma (LX-1 and GI-117), ovarian carcinoma (GI-102),and pancreatic adenocarcinoma (GI-103). The MTSP12 transcript was weaklydetected in prostatic adenocarcinoma (PC3). The MTSP12 transcript wasalso detected in CWR22R prostate tumor grown on nude mice. No apparentsignal was detected in two forms of colon adenocarcinomas (GI-112 andCX-1).

[0333] MTSP20

[0334] MTSP20 is expressed in the lung, colon, cervical tumors and inleukemic cells. It may also be expressed in breast, ovarian, pancreatic,prostate and in other tumors. MTSP20 transcript was detected in liver,lymph node, cerebellum, pancreas, prostate, uterus, testis, glands(adrenal, thyroid and salivary), thymus, kidney and spleen. Lowertranscript level was found in lung, placenta, bladder, ovary, digestivesystem, circulatory system and other parts of the the brain. MTSP20 isalso expressed in certain tumor cell lines including lung carcinoma(A519), colorectal carcinoma (SW480), lymphoma (Raji and Daudi),cervical carcinoma (HeLaS3) and leukemia (HL-60, K-562 and MOLT-4) celllines.

[0335] MTSP22

[0336] MTSP22 is expressed in the uterine tissue, thymus, adiposetissue, and lymph node. It may also be expressed in lung, stomach,uterine, breast, ovarian, prostate and in other tumors. MTSP22transcript was detected in some uterus tissue samples, but not in theirmatched tumor samples. In one of 42 uterus samples, MTSP22 is expressedin tumor and its metastatic tissues, but not in the normal tissuecounterpart. MTSP22 is also expressed in some stomach tumors and lungtumors, but not in their normal tissue counterparts. MTSP22 is alsoexpressed in the normal tissue of a pancreas matched cDNA pair.MTSP22-encoding cDNA was detected in thymus, adipose tissue, and lymphnode

[0337] MTSP25

[0338] MTSP25 is expressed in breast, colon, uterine, ovarian, kidney,prostate, testicular cancer tissue. It may also be expressed in lung,stomach, prostate and in other tumors. MTSP25 transcript was expressedweakly in the lymph node. In the cancer profiling array analysis, MTSP25is highly expressed in prostate samples (in normal and cancer samples).MTSP25 was highly expressed in a kidney tumor sample, but not in itsnormal tissue counterpart. MTSP25 was also expressed a breast cancersamples, but not in its normal tissue counterpart. MTSP25 was expressedin normal uterus samples, but not in their tumor counterparts. MTSP25expression was also ovarian cancer samples. Among these three samples,the expression of MTSP25 was also detected in one of the matched normaltissue counterparts. MTSP25 expression was also detected in tumorsamples in colon cDNA pairs.

[0339] PCR analysis revealed that MTSP25 cDNA was strongly detected intestis and mammary gland adenocarcinoma, weakly detected in brain,placenta, lung, spleen, prostate, small intestine, colon, and leukocyte,and very weakly detected in heart, liver and pancreas.

[0340] 2. Endotheliases

[0341] Endotheliases are a class of cell surface proteases that areexpressed on cells, particularly endothelial cells, particularly thoseproliferating endothelial cells, which are involved in a variety ofproliferative processes, including undesirable angiogenesis associatedwith tumor growth and metastasis, and with other hyperproliferativedisorders, such as restenosis, scarring, diabetic retinopathies,diseases and disorders of the anterior eye (see, U.S. application Ser.No. 09/717,473, filed Nov. 20, 2000, and International PCT applicationNo. PCT/US00/31803).

[0342] Proliferative Diseases

[0343] Endotheliases are particularly useful targets for delivery oftherapeutic agents for treatment of any disorder involving aberrantangiogenesis. Endothelial cells play a key role in angiogenesis, whichis is the generation of new blood vessels from parent microvessels.Angiogenesis plays a major role in the metastasis of cancer and in thepathology of a variety of other disorders.

[0344] Controlled and uncontrolled angiogenesis proceed in a similarmanner. Endothelial cells and pericytes, surrounded by a basementmembrane, form capillary blood vessels. Angiogenesis begins with theerosion of the basement membrane by enzymes released by endothelialcells and leukocytes. The endothelial cells, which line the lumen ofblood vessels, then protrude through the basement membrane. Angiogenicstimulants induce the endothelial cells to migrate through the erodedbasement membrane. The migrating cells form a “sprout” off the parentblood vessel, where the endothelial cells undergo mitosis andproliferate. The endothelial sprouts merge with each other to formcapillary loops, creating the new blood vessel.

[0345] Angiogenesis, Modulators and Associated Diseases

[0346] Angiogenesis is highly regulated by a system of angiogenicstimulators and inhibitors. Known examples of angiogenesis stimulatorsinclude certain growth factors, cytokines, proteins, peptides,carbohydrates and lipids (Norrby (1997) APMIS 105:417-437); Polverini(1995) Crit. Rev. Oral. Biol. Med. 6:230-247). A variety of endogenousand exogenous angiogenesis inhibitors are known in the art (Jackson etal. (1997) FASEB 11:457-465; Norrby (1997) APMIS 105:417-437); andO'Reilly (1997) Investigational New Drugs, 15:5-13).

[0347] Angiogenesis is essential for normal placental, embryonic, fetaland post-natal development and growth, but almost never occursphysiologically in adulthood except in very specific restrictedsituations. For example, angiogenesis is normally observed in woundhealing, fetal and embryonal development and formation of the corpusluteum, endometrium and placenta. Angiogenesis in the adult is oftenassociated with disease states.

[0348] Persistent, unregulated angiogenesis occurs in a multiplicity ofdisease states, tumor metastasis and abnormal growth by endothelialcells and supports the pathological damage seen in these conditions. Thediverse pathological disease states in which unregulated angiogenesis ispresent have been grouped together as angiogenic dependent or angiogenicassociated diseases.

[0349] The control of angiogenesis is altered in certain disease statesand, in many cases, the pathological damage associated with the diseaseis related to uncontrolled angiogenesis (see generally, Norrby (1997)APMIS 105:417-437); and O'Reilly (1997) Investigational New Drugs15:5-13). Thus, angiogenesis is involved in the manifestation orprogress of various diseases, for example, various inflammatorydiseases, such as rheumatoid arthritis, psoriasis, diabeticretinopathies, certain ocular disorders, including recurrence ofpterygii, scarring excimer laser surgery and glaucoma filtering surgery,various disorders of the anterior eye, cardiovascular disorders, chronicinflammatory diseases, wound repair, circulatory disorders, crestsyndromes, dermatological disorders (see, e.g., U.S. Pat. Nos.5,593,990, 5,629,327 and 5,712,291) and notably cancer, including solidneoplasms and vascular tumors. Angiogenesis is essential for the growthand persistence of solid tumors and their metastases. Repressing,eliminating or modulating this activity, should impact the etiology ofthese diseases and serve as a point of therapeutic intervention. In thedisease state, prevention of angiogenesis could avert the damage causedby the invasion of the new microvascular system. Therapies directed atcontrol of the angiogenic processes could lead to the abrogation ormitigation of these diseases. Hence there is a need to developtherapeutics that target angiogenesis and modulate, particularly,inhibit aberrant or uncontrolled angiogenesis.

[0350] Hence conjugates that contain endotheliase substrates can be usedto deliver therapeutic agents for the treatment of diseases including,but are not limited to, rheumatoid arthritis, psoriasis, diabeticretinopathies, other ocular disorders, including recurrence of pterygii,scarring from excimer laser surgery and glaucoma filtering surgery,various disorders of the anterior eye, cardiovascular disorders,autoimmune diseases, chronic inflammatory diseases, wounds, circulatorydisorders, crest syndromes, restenosis, psoriasis and otherdermatological disorders (see, e.g., U.S. Pat. Nos. 5,593,990, 5,629,327and 5,712,291) and notably cancer, including solid neoplasms andvascular tumors.

[0351] Endotheliases 1 and 2

[0352] Exemplary of endotheliases are two different endotheliases andvariant forms thereof designated endotheliase 1 and endotheliase 2 (seeSEQ ID Nos. 21-27. Other members of the family can be identified byprobing for genes or searching libraries for genes that have sequenceidentity, particularly at least 40%, 60%, 80%, 90%, 95%, 98% or greatersequence identity to the protease domain of an endotheliase identifiedherein, or that hybridize under conditions of high stringency to thefull-length of the nucleic acid encoding a protease domain of anendotheliase provided herein, and that are expressed on endothelialcells.

[0353] Alternatively, and as a way of identifying endotheliases that canhave lower sequence identity, an endotheliase can be identified by themethods, such by identifying ESTs or other nucleic acid fragments thathave sequences similar to a protease and then using such fragments asprobes to identify and select cDNA clones encoding full-length proteasesor protease domains thereof, identifying those that have thecharacteristics of transmembrane proteins, and then determining the geneexpression profile to identify those that are expressed on the surfaceof endothelial cells. Encoded proteins that have protease activity, thatinclude a transmembrane domain and an extracellular domain, and that areexpressed in endothelial cells are endotheliases. Any method foridentification of genes encoding proteins (or proteins) that encode atransmembrane protease expressed on an endothelial cell is contemplatedherein.

[0354] Endotheliase 1

[0355] Exemplary of the endotheliase are endotheliase 1 and endotheliase2. These are expressed on endothelial cells. Exemplary of a full-lengthendotheliase 1 is one that includes the sequence of amino acids setforth in SEQ ID No. 42 (see, International PCT application No. WO00/5006, which describes a gene it designates DESC1 that is expressed insquamous cell carcinomas and prostate tumors). As noted endotheliasesare expressed on endothelial cells. A protease domain thereof is setforth in SEQ ID NO: 22.

[0356] Expression Profile of Endotheliase 1

[0357] To obtain information regarding the tissue distribution ofendotheliase 1, the DNA insert of clone H117 was used to probe an RNAblot composed of 76 different human tissues (catalog number 7775-1;human multiple tissue expression (MTE) array; CLONTECH, Palo Alto,Calif.). Significant expression was observed in the esophagus, withminor expression levels in the stomach, salivary gland, pancreas,prostate, bladder, trachea and uterus. Northern analysis using RNA blots(catalog numbers 7765-1 & 7782-1; human muscle and digestive systemmultiple tissue northern (MTN) blots; CLONTECH) confirmed that theexpression was restricted to the esophagus. Two transcripts(approximately 1.7 and 2 kb) were detected in the esophagus.Endotheliase 1 also is expressed in umbilical vein endothelial cells,PC3 and LnCAP cells.

[0358] Endotheliase 2 and Nucleic Acids Encoding Endotheliase 2

[0359] Two splice variant forms of endotheliase 2 designatedendotheliase 2-S and endotheliase 2-L are exemplified herein (see SEQ IDNos. 23-26). The open reading frame of the nucleic acid encodingendotheliase 2-S (SEQ ID No. 23) is composed of 1,689 bp, whichtranslates to a 562-amino acid protein (SEQ ID No. 24), while the ORF ofendotheliase 2-L is composed of 2,067 bp (SEQ ID No. 25), whichtranslates to a 688-amino acid protein (SEQ ID No. 26).

[0360] The nucleic acid encoding the protease domain of endotheliase 2-Sis composed of 729 bp which translates to a 242-amino acid protein(amino acids 321-562 of SEQ ID Nos. 23 and 24), while that ofendotheliase 2-L is composed of 1,107 bp, which translates to a368-amino acid protein (amino acids 321-688 of SEQ ID Nos. 25 and 26).

[0361] Endotheliase-2 Proteins

[0362] Any and all of the above-noted endotheliases and/or proteasedomains thereof, such as those that include the sequences of amino acidsin SEQ ID Nos. 22, 24, 26 and 27 or are encoded by nucleic acid thathybridize thereto under the conditions as described above arecontemplated for use in the methods herein. Also contemplated herein areproteins that include amino acid sequence changes, such as those setforth in Table 1 above, and retain protease activity.

[0363] Gene Expression Profile and Transcript Size of Endotheliase 2 inNormal and Tumor Tissues

[0364] In addition to expression in endothelial cells, endotheliase 2 isexpressed in placenta, pancreas, thyroid gland, liver and lung tissues.It also is expressed at lower levels in mammary gland, salivary gland,kidney, trachea, esophagus, appendix, heart and fetal lung. Endotheliase2 also is expressed in several tumor cell lines and, hence, in certaintumors, including lung and colon, including breast carcinoma, lungcarcinomas, colon adenocarcinomas, pancreatic adenocarcinoma (GI-103),and ovarian carcinoma. It has also been detected in prostate andfibrosarcoma cell lines.

C. Conjugates

[0365] Conjugates that are substrates for proteases on the surfaces ofcells, particularly serine proteases, including type II membrane-boundserine proteases, and endotheliases are provided. Any cell surfaceprotease, including cell-associated or localized proteases, iscontemplated herein. Generally proteases expressed at high levels inactive forms in essential tissues are not ideal target candidates. Theproteases include those that are expressed on relatively limited numbersof cells or that are expressed at high levels in cells, such as tumorcells and endothelial cells and immune cells, that are involved indisease states or are present in diseases states in the locale of cellsinvolved in the disease states. For example, endothelial cells by virtueof their role in angiogenesis are involved in numerous proliferativedisorders; immune cells are involved in many disease processes includingcancers and diseases and inflammatory disorders. Other cell surfaceproteases are expressed at higher levels in certain tumors than innormal cells. Whether or not such proteases have a role in the disordertheir higher expression in cells involved in a disease state issufficient for use for targeting therapeutic agents in the conjugatesprovided herein.

[0366] The conjugates, which contain a therapeutic agent, such as acytotoxic agent, is activated upon cleavage by a cell surface protease,including cell-associated and cell-localized proteses. Exemplary of suchproteases are the MTSPs, such as, but not limited to, MTSP1, MTSP3,MTsP4, MTSP6, MTSP7, MTSP9, MTSP10, MTSP12, MTSP20, MTSP22, MTSP25,urokinases and endotheliases. Hence, the conjugates targeted to suchproteases are prodrugs in that the therapeutic agent is inactive asadministered and is ultimately activated in the vicinity of the targetedcell or tissue. Although cell surface proteases, such as transmembraneproteases, are the intended targets, any released, shed or soluble formsof the proteases and others also can be targeted.

[0367] Thus, the conjugates, which contain a therapeutic agent, such asa cytotoxic agent, are substantially inactive prior to action by a cellsurface protease, a peptidic moiety that is a substrate for a targetedcell surface protease (i.e., a peptidic substrate), and, optionally, alinker. The therapeutic agents in the conjugates are activated uponcleavage of the peptidic substrate of the conjugate by a cell surfaceprotease. The therapeutic agents, such as cytotoxic agents, are releasedas the free yagent, or, alternatively, are released coupled to theportion of the peptidic substrate (P1-P2-P3-etc. (i.e., the N-terminus)or P1′-P2′-etc. (i.e., the C-terminus) that the agents were linked to inthe conjugate, optionally via a linker. The cytotoxic agents, in theseforms, are released in the vicinity of cells that express the proteases.Activation is effected, in certain embodiments, because the therapeuticagent, such as cytotoxic agent, following action of the cell surfaceprotease, can cross the cell membrane or otherwise interact with thecell or tissue and exhibit therapeutic activity. In other embodiments,any remaining peptidic moieties or amino acids can be cleaved fromtherapeutic agent to render it active. The conjugates act as prodrugsbecause the therapeutic agents when conjugated are substantiallyinactive. Upon cleavage by the targeted protease, the therapeutic agentis released either in active form or in a form that is activated by thetargeted cell, tissue or surrounding environment.

[0368] In one exemplary embodiment, the targeted agent is a cytotoxicagent and the conjugates for use in the methods and compositionsprovided herein have the formula:

(peptide^(l))_(s)-(linker)_(q)-(cytotoxic agent)_(t)

[0369] or a derivative thereof, where peptide^(l) is a peptidicsubstrate for a cell surface protease or a released, shed or otherwiseunbound membrane protease, such as an MTSP; s is greater than or equalto 1, or is 1 to 6, or is 1 or 2, or is 1; linker is any linker; q isgreater than or equal to 0, or is 0 to 4, or is 0 or 1; the cytotoxicagent is an anti-tumor, anti-cancer or anti mitotic agent, includinganti-antiangiogenic agents; and t is 1 or more, or is 1 or 2. In theseconjugates, the cytotoxic agent is covalently attached, optionally via alinker, to either the C-terminus or the N-terminus of the peptidicsubstrate. In embodiments where the therapeutic agent, such as acytotoxic agent, is attached to the C-terminus of the peptidicsubstrate, the N-terminus optionally is capped. N-Terminal caps for useherein include, but are not limited to, acyl, sulfonyl and carbamoylgroups. In embodiments where the therapeutic agent is attached to theN-terminus of the peptidic substrate, the C-terminus is a carboxamidederivative.

[0370] In certain embodiments, peptide^(l) is a peptidic substrate for acell surface protease or a soluble MTSP whereby, upon action of theprotease, the conjugate, which is substantially inactive, is cleaved atthe P1-P1′ bond to release a compound of the formula:

(peptide^(a))_(s)-(linker)_(q)-(therapeutic agent)_(t)

[0371] or a derivative thereof, that exhibits therapeutic activity, suchas cytotoxic activity in vitro and in vivo. In these compounds,peptide^(a) is a truncated version of peptide^(l) resulting fromcleavage at the P1-P1′ bond.

[0372] In another embodiment, the conjugates for use in the methods andcompositions provided herein possess two therapeutic agents, such ascytotoxic agents, which are the same or different, linked to theC-terminus and the N-terminus, respectively, optionally via linkerslinker¹ and linker², of a peptidic substrate for cell surface proteaseor a soluble MTSP. In this embodiment, the conjugates have the formula:

(therapeuticagent¹)_(x)-(linker¹)_(w)-(peptide^(l))_(s)-(linker²)_(q)-(therapeuticagent²)_(t)

[0373] or a derivative thereof, where peptide^(l) is a peptidicsubstrate for a cell surface protease, or a soluble MTSP; s is greaterthan or equal to 1, or is 1 to 6, or is 1 or 2, or is 1; linker¹ andlinker² are each independently any linker and are the same or different;q and w are each independently greater than or equal to 0, or are 0 to4, or are 0 or 1; the therapeutic agents, which are the same ordifferent, are anti-tumor, anti-cancer or anti mitotic agents; and t andx are each independently 1 or more, or are 1 or 2.

[0374] In these embodiments, peptide^(l) is a peptidic substrate for acell surface protease or a soluble MTSP whereby, upon action of theprotease, the conjugate, which is substantially inactive, is cleaved ata point on the peptidic chain to release two compounds of the formulae:

(therapeutic agent¹)_(x)-(linker¹)_(w)-(peptide^(a1))_(s); and

(peptide^(a2))_(s)-(linker²)_(q)-(therapeutic agent²)_(t)

[0375] or derivatives thereof. The released therapeutic agents areactive or are further activated by the cell, tissue or surroundingenvironment. In these compounds, peptide^(a1) and peptide^(a2) areN-terminal and C-terminal truncated portions, respectively, ofpeptide^(l) resulting from cleavage at the P1-P1′ bond.

[0376] In one embodiment, the conjugates for use in the compositions andmethods provided herein have formula I:

X^(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(L)_(n)-Z

[0377] or a derivative thereof, where Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows:

[0378] l is 0 or 1; when l is 0, j, i, p and m are 0; when l is 1, j is0 or 1; when j is 0, i, p and m are 0; when j is 1, i is 0 or 1; when iis 0, p and m are 0; when i is 1, p is 0 or 1; when p is 0, m is 0; whenp is 1, m is 0 or 1;

[0379] u, k and r are selected as follows:

[0380] u is 0 or 1; when u is 0, k and r are 0; when u is 1, k is 0 or1; when k is 0, r is 0; when k is 1, r is 0 or 1;

[0381] n is 0 or 1; X^(n) is hydrogen, or an acyl, sulfonyl or carbamoylcap; and P6 to P3′ are amino acid residues, as defined below. In thisembodiment, the P6 to P3′ residues are linked by peptide bonds orpeptide bond surrogates. Thus, the P6 to P3′ portion of the conjugate isa peptidic substrate, as defined herein.

[0382] In another embodiment, the conjugates for use in the compositionsand methods provided herein have formula II:

Z-(L)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-X^(c)

[0383] or a derivative thereof, where Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows:

[0384] l is 0 or 1; when l is 0, j, i, p and m are 0; when l is 1, j is0 or 1; when j is 0, i, p and m are 0; when j is 1, i is 0 or 1; when iis 0, p and m are 0; when i is 1, p is 0 or 1; when p is 0, m is 0; whenp is 1, m is 0 or 1;

[0385] u, k and r are selected as follows:

[0386] u is 0 or 1; when u is 0, k and r are 0; when u is 1, k is 0 or1; when k is 0, r is 0; when k is 1, r is 0 or 1;

[0387] n is 0 or 1; X^(c), together with the carbonyl group of the aminoacid residue to which it is attached, forms a carboxylic acid or acarboxamide group; and P6 to P3′ are amino acid residues, as definedbelow. In this embodiment, the P6 to P3′ residues are linked by peptidebonds or peptide bond surrogates. Thus, the P6 to P3′ portion of theconjugate is a peptidic substrate, as defined herein.

[0388] In a further embodiment, the conjugates for use in thecompositions and methods provided herein have formula III:

Z¹-(L¹)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)(L²)_(v)-Z²

[0389] or a derivative thereof, where Z¹ and Z² are each therapeuticagents and are the same or different; L¹ and L² are each linkers and arethe same or different; l, j, i, p and m are selected as follows:

[0390] l is 0 or 1; when l is 0, j, i, p and m are 0; when l is 1, j is0 or 1; when j is 0, i, p and m are 0; when j is 1, i is 0 or 1; when iis 0, p and m are 0; when i is 1, p is 0 or 1; when p is 0, m is 0; whenp is 1, m is 0 or 1;

[0391] u, k and r are selected as follows:

[0392] u is 0 or 1; when u is 0, k and r are 0; when u is 1, k is 0 or1; when k is 0, r is 0; when k is 1, r is 0 or 1;

[0393] n and v are each independently 0 or 1; and P6 to P3′ are aminoacid residues, as defined below. In this embodiment, the P6 to P3′residues are linked by peptide bonds or peptide bond surrogates. Thus,the P6 to P3′ portion of the conjugate is a peptidic substrate, asdefined herein.

[0394] In another embodiment, the conjugates for use in the compositionsand methods provided herein have formula IV:

X^(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(P4′)_(s)-(L)_(n)-Z

[0395] or a derivative thereof, where Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows:

[0396] l is 0 or 1; when l is 0, j, i, p and m are 0; when l is 1, j is0 or 1; when j is 0, i, p and m are 0; when j is 1, i is 0 or 1; when iis 0, p and m are 0; when i is 1, p is 0 or 1; when p is 0, m is 0; whenp is 1, m is 0 or 1;

[0397] u, k, r and s are selected as follows:

[0398] u is 0 or 1; when u is 0, k, r and s are 0; when u is 1, k is 0or 1; when k is 0, r and s are 0; when k is 1, r is 0 or 1; when r is 0,s is 0; when r is 1, s is 0 or 1;

[0399] n is 0 or 1; X^(n) is hydrogen, or an acyl, sulfonyl or carbamoylcap; and P6 to P4′ are amino acid residues, as defined below. In thisembodiment, the P6 to P4′ residues are linked by peptide bonds orpeptide bond surrogates. Thus, the P6 to P4′ portion of the conjugate isa peptidic substrate, as defined herein. In another embodiment, theconjugates for use in the compositions and methods provided herein haveformula V:

Z-(L)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(P4′)_(s)-X^(c)

[0400] or a derivative thereof, where Z is a therapeutic agent; L is alinker; i, j, i, p and m are selected as follows:

[0401] l is 0 or 1; when l is 0, j, i, p and m are 0; when l is 1, j is0 or 1; when j is 0, i, p and m are 0; when j is 1, i is 0 or 1; when iis 0, p and m are 0; when i is 1, p is 0 or 1; when p is 0, m is 0; whenp is 1, m is 0 or 1;

[0402] u, k, r and s are selected as follows:

[0403] u is 0 or 1; when u is 0, k, r and s are 0; when u is 1, k is 0or 1; when k is 0, r and s are 0; when k is 1, r is 0 or 1; when r is 0,s is 0; when r is 1, s is 0 or 1;

[0404] n is 0 or 1; X^(c), together with the carbonyl group of the aminoacid residue to which it is attached, forms a carboxylic acid or acarboxamide group; and P6 to P4′ are amino acid residues, as definedbelow. In this embodiment, the P6 to P4′ residues are linked by peptidebonds or peptide bond surrogates. Thus, the P6 to P4′ portion of theconjugate is a peptidic substrate, as defined herein.

[0405] In a further embodiment, the conjugates for use in thecompositions and methods provided herein have formula VI:

Z¹-(L¹)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(P4′)_(s)-(L²)_(v)-Z²

[0406] or a derivative thereof, where Z¹ and Z² are each therapeuticagents and are the same or different; L¹ and L² are each linkers and arethe same or different; l, j, i, p and m are selected as follows:

[0407] l is 0 or 1; when l is 0, j, i, p and m are 0; when l is 1, j is0 or 1; when j is 0, i, p and m are 0; when j is 1, i is 0 or 1; when iis 0, p and m are 0; when i is 1, p is 0 or 1; when p is 0, m is 0; whenp is 1, m is 0 or 1;

[0408] u, k, r and s are selected as follows:

[0409] u is 0 or 1; when u is 0, k, r and s are 0; when u is 1, k is 0or 1; when k is 0, r and s are 0; when k is 1, r is 0 or 1; when r is 0,s is 0; when r is 1, s is 0 or 1;

[0410] n and v are each independently 0 or 1; and P6 to P4′ are aminoacid residues, as defined below. In this embodiment, the P6 to P4′residues are linked by peptide bonds or peptide bond surrogates. Thus,the P6 to P4′ portion of the conjugate is a peptidic substrate, asdefined herein.

[0411] Exemplary peptidic substrates, therapeutic agents, linkers andexemplary conjugates of formulae I-VI are described in further detailbelow. It is intended herein that conjugates resulting from allcombinations and/or permutations of the groups recited below for thevariables of formulae I-VI are encompassed within the instantdisclosure.

[0412]1. Peptidic Substrates

[0413] The peptidic substrates contemplated for use in the conjugatesare substrates for the targeted cell surface protease or a soluble, shedor released form thereof, and contain a sufficient number of amino acidresidues to render any therapeutic agent in the conjugate substantiallyinactive. In the exemplary embodiment where the therapeutic agent is,for example, doxorubicin, the conjugate is substantially inactive byvirtue of the inability of the conjugated therapeutic agent to cross thecell membrane. In certain embodiments, the peptidic substrate containsat least 1, 2, 3, 4 or 5 amino acid residues, and can contain up to nineor ten residues. Longer peptidic substrates can be used in theconjugates as long as upon cleavage, the resulting therapeutic agent ortherapeutic agent-amino acid or -peptidic moiety conjugate exhibits thedesired therapeutic effect in vivo and in vitro.

[0414] Hence, exemplary peptidic substrates for use in the conjugatesprovided herein possess at least one amino acid (P1), two amino acids(P1-P1′), three amino acids (P2-P1-P1′) and typically contain four, fiveor six amino acid residues (P3-P2-P1-P1′, P4-P3-P2-P1-P1′ orP4-P3-P2-P1-P1′-P2′), where the P1-P1′ bond is the site of cleavage ofcell surface protease, or a soluble, shed or released form thereof,including, but not limited to, a cell surface protease, such as a serineprotease, including, for example, but not limited to, uPA bound to itsreceptor, MTSPs and endotheliases. The peptidic substrates optionallyfurther possess a P5, P6 or P3′ amino acid residue, and, in certainembodiments, possess P7, P8, P9, P10, P4′, P5′, P6′ residues. Thus, thepeptidic substrates for use in the conjugates provided herein arepenta-, hexa-, hepta-, octa- and nona-peptidic substrates, and cancontain 10, 11, 12, 13, 14, 15 or more residues as long as, uponcleavage of the conjugate by the protease, the resulting therapeuticagent or therapeutic agent-amino acid or -peptidic moiety conjugateexhibits the desired therapeutic effect in vivo and in vitro.

[0415] The peptidic substrates are conjugated to the therapeutic agent(or to a linker to which the therapeutic agent is linked) via theC-terminal residue (i.e., P1′, P2′ or P3′), or the N-terminal residue(i.e., P6, P5 or P4), or optionally an internal residue. The peptidicsubstrates, for example, can be straight chains, but can be cyclized orinclude cyclized portions.

[0416] In embodiments where the conjugation is via the C-terminus of thepeptidic substrate, the peptidic substrate optionally possesses a cap,such as an acyl or carbamoyl cap at the N-terminus. In embodiments whereconjugation is via the N-terminus of the peptidic substrate, thepeptidic substrate further possess a terminal group, such as acarboxamide group, at the C-terminus.

[0417] The conjugates can contain a plurality of peptidic substrates anda plurality of therapeutic agents. For example, in conjugates thatcontain two therapeutic agents, which are the same or different,conjugation to the therapeutic agent(s) or linker linked thereto can bevia the C-terminal and N-terminal residues of the peptidic substrate.

[0418] The methods described for selection of substrates above can beused to design suitable substrates. In addition, substrates can bedesigned based upon known specificities of other proteases. For example,the specificities of trypsin-like and trypsin family members can aid indesign of possible substrates. The following summarizes substratepreferences for particular serine proteases (see, e.g., Harris et al.(2000) PNAS 97(14):7754-7759). EXEMPLARY EXEMPLARY EXEMPLARY PROTEASE P1RESIDUE(S) P2 RESIDUE(S) P3 RESIDUE(S) Chymotrypsin Tyr, Phe, Trp — —Trypsin Arg, Lys — — Thrombin Arg, Lys Phe Thr, Trp Plasmin Lys, ArgTrp, Tyr, Met Gln Granzyme B Asp — — Human Ala, Val, Ile — — NeutrophilElastase Tissue Arg Ser, Gly, Ala Met, Tyr Plasminogen Factor UrokinaseArg Ser, Ala Thr, Ser Factor Xa Arg Gly —

[0419] Typical protocols for preparation of the conjugates can includethe steps of: 1) identification of a targeted protease; 2) expressionand assay development; 3) substrate selection, such as, for example, bytesting chromogenic or fluorogenic substrates to identify those cleavedby a selected target protease, by use of substrate phage display toidentify peptidic substrates cleaved by a targeted protease, by use of anatural protein or peptide substrate or a natural inhibitor of theprotease, and by use of combinatorial libraries to identify substratescleaved by a targeted protease; 4) synthesis of conjugates containingthe identified substrate; and 5) biological evaluation thereof,including, but not limited to, in vitro assays, cell culture assays,biological assays, and in vivo animal models (see, e.g., EXAMPLE 10).

[0420] A conjugate can be designed by any methods known to those ofskill in the art. The following provides an exemplary protocol. First, aseries of commercially available chromogenic and fluorogenic peptidicsubstrates can be tested for cleavage by the protease of interest (seeExamples for lists of exemplary chromogenic and fluorogenic substratesand the table below). The peptidic portion of these substrates occupiesthe unprimed binding sites of the protease while the reporter group islocated on the primed side of the scissle bond. Effective conjugates canthen be designed based on the structure of the substrates that areefficiently cleaved by the protease.

[0421] The peptidic portion of these efficiently cleaved substrates canbe used as the unprimed region of the conjugate, and Ser-therapeuticagent, such as a cytotoxic agent (e.g., doxorubicin),Ser-Leu-therapeutic agent or Ser-Ser-Leu-therapeutic agent can be usedas the primed region of the conjugate. Cleavage of these conjugateprodrugs releases either Ser-therapeutic agent, Ser-Leu-therapeuticagent or Ser-Ser-Leu-therapeutic agent compounds. In another embodiment,the Ser in the released Ser-therapeutic agent may be replaced by otheramino acid residues including, but not limited to, Ala, hSer, Abu, Thr,Met, nLeu and Val. In another embodiment, such as when the therapeuticagent is doxorubicin, the amino acid residue conjugated to thetherapeutic agent possesses a hydrophobic side chain. Such amino acidresidues include, but are not limited to, Leu, Abu, nLeu, nVal, CHA,hCHA, (hex)Gly, (allyl)Gly, (propargyl)Gly and (cyclopropyl)Ala. Inanother embodiment, such as when the therapeutic agent is taxol, theamino acid residue conjugated to the therapeutic agent possesses a sidechain that is not sterically bulky. Such amino acid residues include,but are not limited to, Gly and Ala. The resulting P1′-therapeuticagent, P1′-P2′-therapeutic agent, or P1′-P2′-P3′-therapeutic agentcompound can be further processed in vivo into active therapeuticagents.

[0422] Another approach to designing a conjugate prodrug for a proteasesubstrate is to use substrate phage display to elucidate optimal subsiteoccupancy for the protease. The resulting information can then be usedto design the peptidic, unprimed portion of the conjugate. As describedabove, the primed region of the conjugate can be fixed asSer-therapeutic agent, Ser-Leu-therapeutic agent orSer-Ser-Leu-therapeutic agent.

[0423] A third approach to design an effective prodrug conjugateinvolves the use of combinatorial fluorogenic substrate libraries todetermine optimal residues for the unprimed region of a proteasesubstrate. These selected sequences can then be used as the unprimedportion of the conjugate prodrug and, and Ser-therapeutic agent, (e.g.,doxorubicin), Ser-Leu-therapeutic agent or Ser-Ser-Leu-therapeutic agentcan be used as the primed region of the conjugate. These methods havebeen used in the design of the peptidic substrate portion of theconjugates provided herein. For example, sequences including GSGR (andrelated sequences such as TGR, SGR, extended variants and others herein)were based on or dervied from substrate phage display experiments usingu-PA as the taret protease. Many matriptase conjugates, such as(R/K)-X-S-R and X-(R/K)-S-R, and related sequences as provided herein,were based on data from combinatorial libraries. In other embodiemnts,seqeuence sequences in natural substrates or natural inhibitors of aprotease target, such as uPA, including VSAR, PGR (from P3-P1 ofplasminogen) and related sequences, were used in design of u-PA-targetdconjugates. In other embodiments, sequences from chromgenic substrates,such as D-HHT-Gly-Arg, and related sequences, were used for design ofET-1-targeted conjugates.

[0424] Chromogenic/Fluorogenic Substrates Chromogenic/fluorogenicsubstrates Enzyme Substrate Structure MTSP1 Spectrozyme t-PACH₃SO₂-D-HHT-Gly-Arg-pNA.AcOH MTSP1 S 2765 N-α-Z-D-Arg-Gly-Arg-pNA.2HClMTSP3 Spectrozyme fXIIa H-D-CHT-Gly-Arg-pNA.2AcOH MTSP4^(a) Spec PLH-D-Nle-HHT-Lys-pNA.2AcOH MTSP5 S 2765 N-α-Z-D-Arg-Gly-Arg-pNA.2HClMTSP6 spectrozyme t-PA CH₃SO₂-D-HHT-Gly-Arg-pNA.AcOH MTSP7 S 2366pyroGlu-Pro-Arg-pNA.HCl MTSP9 Pefachrome fVIIa CH₃SO₂-D-CHA-But-Arg-pNAMTSP10 spectrozyme t-PA CH₃SO₂-D-HHT-Gly-Arg-pNA.AcOH MTSP22 S 2366pyroGlu-Pro-Arg-pNA.HCl ET-1 spectrozyme t-PACH₃SO₂-D-HHT-Gly-Arg-pNA.AcOH ET-2 S 2765 N-α-Z-D-Arg-Gly-Arg-pNA.2HClu-PA S-2444 pyroGlu-Gly-Arg-pNA.HCl

[0425] Briefly, for a coupled assay, the ability of the protease toactivate an enzyme, such as plasminogen or trypsinogen is tested. Toperform these assays, a protease is incubated with a zymogen, such asplasminogen or trypsinogen, in the presence of a labelled knownsubstrate, such as lys-plasminogen or Spec PL (for plasmin), for thezymogen. If protease activates the zymogen, the activated enzyme, suchas plasmin and trypsin, will degrade the substrate, thereby changing thespectral properties of the substrate.

[0426] Exemplary Peptidic Substrates

[0427] The following description provides exemplary peptidic substratesfor cleavage by proteases, such as MTSP1 (or matriptase), endotheliase 1and urokinase, and a general discussion of properties of the residues.In a similar manner, peptidic substrates for cleavage by other cellsurface proteases, or a soluble, shed or released form thereof, can besimilarly designed by identifying peptidic substrates for the selectedprotease and then preparing conjugates that contain such peptidicsubstrates.

[0428] a. The P1 Residue

[0429] Amino acid residues for use at the P1 position of the peptidicsubstrates for use in the conjugates provided herein include Arg, Argsurrogates and Lys. Arg surrogates include unnatural amino acids thatpossess a group or moiety that functions in substantially the same wayas the naturally occurring side chain of arginine to achievesubstantially the same result (e.g., acting as the P1 residue in asubstrate for a MTSP1, urokinase or endotheliase). Arg surrogatesinclude, but are not limited to, α-amino acids that possess as the sidechain any of the following: the side chain of homoarginine;guanidinoaminopropyl; guanidinoaminoethyl; (Me)₂arginine side chain;(Et)₂arginine side chain; (4-aminomethyl)phenylmethyl;4-amidinophenylmethyl; 4-guanidinophenylmethyl; or the Arg surrogate isa conformationally constrained arginine analog such as:

[0430] where z is 0 or 1 (see, e.g., Webb et al. (1991) J. Org. Chem.56:3009); or the side chain is a conformationally constrained arginineside chain analog such as:

[0431] where d is an integer from 0 to 5, or 1 to 3; and W is N or CH;or a mono- or di-substituted N-alkyl derivative of the above groups,where alkyl is, in certain embodiments, lower alkyl, such as, forexample, methyl.

[0432] In certain embodiments herein, the P1 residue is Arg.

[0433] b. The P2 Residue

[0434] In the conjugates provided herein, the P2 residue is selectedfrom Phe, Ser, Gly, Ala, Ser(OMe), hSer, 1-methylHis, 3-methylHis, His,nVal, nLeu, Abu, (hS)Gly, Thr, Aib, CHA and Tyr. In another embodiment,the P2 residue is selected from Phe, Ser, Gly and Ala. In certainembodiments herein, the P2 residue is Ser or Ala. In another embodiment,the P2 residue is Gly or Ala.

[0435] c. The P3 Residue

[0436] Amino acid residues for use at the P3 position of the conjugatesprovided herein include Arg, Lys, Gln, Quat, Arg surrogates, Ser, Thr,hSer, dSer, Pro, (hS)Gly, Tyr, 4,4-dimethylThr, Asn, Met(O₂), Quat²,Quat³, Quat⁴ and Quat⁵. In another embodiment, the P3 residue isselected from Arg, Lys, Gln, Quat and Arg surrogates. Arg surrogatesinclude those described above for the P1 residue.

[0437] In certain embodiments, the P3 residue is Gin or Ser.

[0438] d. The P4 Residue

[0439] In the conjugates provided for use in the compositions andmethods provided herein, the P4 residue is selected from Pro, Arg, Ser,Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly, β-Ala,Cys(Me), Gin, t-butylGly and nVal. In another embodiment, the P4 residueis selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Pheand Val. In further embodiments, the P4 residue is selected from Pro,Arg, Ser, Ala, Lys, Gly, nLeu, Phe or Val. In certain embodimentsherein, the P4 residue is Arg or Gly.

[0440] e. The P5 and P6 Residues

[0441] In certain embodiments herein, the peptidic substrates used inthe conjugates contain a P5 and, optionally, a P6 residue. P5 residuesinclude Ile, Arg and Arg surrogates. In another embodiment, P5 residuesinclude Arg and Arg surrogates. Arg surrogates include those describedabove for the P1 residue. P6 residues include, for example, Leu, Val andArg. In another embodiment, P6 residues include, for example, Leu.

[0442] f. The P1′ Residue

[0443] The P1′ residue of the conjugates provided herein is Gly, Ser,Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl,Thr or hSer. In another embodiment, the P1′ residue of the conjugatesprovided herein is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib,Abu, Met or 6-aminohexanoyl. In another embodiment, the P1′ residue isSer, Ala, hSer, Abu, Thr, Met, nLeu or Val. In another embodiment, theP1′ residue is Gly or Ala. In another embodiment, the P1′ residue isSer, Ala or Gly. In another embodiment, the P1′ residue is Leu, Abu,nLeu, nVal, CHA, hCHA, (hex)Gly, (allyl)Gly, (propargyl)Gly or(cyclopropyl)Ala. In certain embodiments herein, the P1′ residue is Ala,Ser, Gly, Ile or d-Ile.

[0444] g. The P2′ Residue

[0445] In certain embodiments herein, the conjugates provided hereinpossess a P2′ residue. P2′ residues for use herein include, but are notlimited to, Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu,Met, 6-aminohexanoyl, hCHA, CHA, hexylGly, allylGly and Phe. In anotherembodiment, P2′ residues for use herein include, but are not limited to,Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl. In another embodiment, the P2′ residue is Ser, hSer,Abu, nLeu, nVal, CHA, hCHA, (allyl)Gly or (hexyl)Gly. In anotherembodiment, the P2′ residue is Gly or Ala. In another embodiment, theP2′ residue is Leu, Abu, nLeu, nVal, CHA, hCHA, (hex)Gly, (allyl)Gly,(propargyl)Gly or (cyclopropyl)Ala. In further embodiments, the P2′residues are Ala, Gly, Ile or d-Ile.

[0446] h. The P3′ Residue

[0447] In other embodiments herein, the peptidic substrates used in theconjugates provided herein include a P3′ residue. P3′ residues for useherein include, but are not limited to, Gly, Ser, Ala, Leu, Ile, nLeu,Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly. In anotherembodiment, the P2′ residue is Ser, hSer, Abu, nLeu, nVal, CHA, hCHA,(allyl)Gly or (hexyl)Gly. In another embodiment, P3′ residues for useherein include, but are not limited to, Gly, Ser, Ala, Leu, Ile, nLeu,Val, nVal, Aib, Abu, Met and 6-aminohexanoyl. In another embodiment, theP3′ residue is Gly or Ala. In another embodiment, the P3′ residue isLeu, Abu, nLeu, nVal, CHA, hCHA, (hex)Gly, (allyl)Gly, (propargyl)Gly or(cyclopropyl)Ala.

[0448] i. The P4′ Residue

[0449] In other embodiments herein, the peptidic substrates used in theconjugates provided herein include a P4′ residue. P4′ residues for useherein include, but are not limited to, Gly, Ser, Ala, Leu, Ile, nLeu,Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly. In anotherembodiment, P4′ residues for use herein include, but are not limited to,Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl. In another embodiment, the P4′ residue is Gly or Ala.In another embodiment, the P4′ residue is Leu, Abu, nLeu, nVal, CHA,hCHA, (hex)Gly, (allyl)Gly, (propargyl)Gly or (cyclopropyl)Ala. Inanother embodiment, the P4′ residue is Leu.

[0450] j. Caps

[0451] 1) X^(n) (the N-terminal Cap)

[0452] In embodiments herein where the therapeutic agent is conjugatedto the C-terminus of the peptidic substrate (i.e., where the conjugatehas formula I), the N-terminus of the peptidic substrate optionally iscapped with an acyl, sulfonyl or carbamoyl derivative. The cap ischosen, in certain embodiments, to increase the hydrophilicity of theconjugate. In embodiments where the peptidic substrate-therapeutic agentconjugate is sufficiently hydrophilic so as not to require furtherhydrophilicity, a non-hydrophilic N-terminal cap, such as an acetylgroup, can be used. In embodiments where increased hydrophilicity isdesired, the N-terminal amino acid is modified with a hydrophilicblocking group. Such blocking groups are chosen based upon the presenceof hydrophilic functionality. Such blocking of the terminal amino groupcan also reduce or eliminate the enzymatic degradation of such peptidyltherapeutic agents by the action of exogenous amino peptidases which arepresent in the blood plasma of warm blooded animals.

[0453] N-Terminal blocking groups that increase the hydrophilicity ofthe conjugates and therefore increase the aqueous solubility of theconjugates include, but are not limited to, hydroxylated alkanoyl,polyhydroxylated alkanoyl, polyethylene glycol, glycosylates, sugars andcrown ethers.

[0454] In certain embodiments herein, the N-terminal blocking group isone of the following:

[0455] a)

[0456] where R¹ and R² are selected from (i) or (ii) as follows:

[0457] (i) R¹ and R² are each independently:

[0458] a) hydrogen;

[0459] b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocyclyl, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, C₁-C₆ perfluoroalkyl, R⁴O—, R³C(O)NR³—, (R³)₂NC(O)—,(R³)₂N—C(NR³)—, R⁴S(O)_(e)NH—, —CN, —NO₂, R³C(O)—, —N₃, —N(R³)₂, orR⁴OC(O)NR³—;

[0460] c) unsubstituted C₁-C₆ alkyl;

[0461] d) substituted C₁-C₆ alkyl wherein the substituent on thesubstituted C₁-C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclyl, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, R³O—, R⁴S(O)_(e)NH—, R³C(O)NR³—,(R³)₂NC(O)—, (R³)₂N—C(NR³)—, —CN, R³C(O)—, —N₃, —N(R³)₂, andR⁴OC(O)—NR³—; or

[0462] (ii) R¹ and R² are combined to form —(CH₂)_(f)— where one of thecarbon atoms optionally is replaced by a moiety selected from: —O—,—S(O)_(e)—, —NC(O)—, —NH— and —N(COR⁴)—;

[0463] R³ is selected from: hydrogen, unsubstituted or substituted aryl,unsubstituted or substituted heterocyclyl, C₁-C₆ alkyl and C₃-C₁₀cycloalkyl;

[0464] R⁴ is selected from: unsubstituted or substituted aryl,unsubstituted or substituted heterocyclyl, C₁-C₆ alkyl and C₃-C₁₀cycloalkyl;

[0465] e is 0, 1 or 2;

[0466] a is 1, 2, 3 or 4;

[0467] b is zero or an integer between 1 and 100; and

[0468] c is 0 to 10, provided that if b is zero, c is 1 to 10; and

[0469] f is 3, 4 or 5.

[0470] In certain embodiments, R¹ and R² are each independentlyhydrogen, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ aralkyl or aryl. In theseembodiments, a is 1, 2, 3 or 4; b is 0 or an integer between 1 and 100;and c is 0 to 10, provided that if b is 0, c is 1 to 10.

[0471] In another embodiment, the N-terminal cap (X^(n)) is hydrogen, or(i), (ii), (iii) or (iv) as follows:

[0472] where R¹ and R² are each independently hydrogen, C₁-C₆ alkyl andaryl; a is 1, 2, 3 or 4; a′ is 0, 1, 2 or 3; b is 0 or an integerbetween 1 and 14; and c is 0 or 1, provided that if b is 0, c is 1.

[0473] In another embodimbent, X^(n) is R³⁰O—C(O)—, R³¹R³²N—C(O)—,R³³(CH₂)_(k)C(O)— or H—C(O)—; where k is an integer from 1 to 4, or is 1or 2; R³⁰ is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R³¹ andR³² are each independently hydrogen, alkyl, aryl, heteroaryl, aralkyl,or heteroaralkyl; and R³³ is hydrogen, hydroxy, alkyl, alkenyl, alkynyl,alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, aralkoxy,heteroaralkyl or heteroaralkoxy.

[0474] In certain embodiments herein, X^(n) is hydrogen, acetyl,hydroxyacetyl, 2,3-dihydroxypropionyl, 2,3,4-trihydroxybutanoyl, PEG(1),PEG(2), PEG(4), PEG(6), PEG(14), PEG(15), PEG(16), PEG(17), PEG(18) orPEG(19). In other embodiments herein, X^(n) is hydrogen, acetyl,hydroxyacetyl, succinyl, quinyl, gallyl, 4-imidazolylacetyl, cotininyl,3-phosphonylpropionyl, gulonyl, 4-phosphonylbutyryl, glutaryl,ethoxysquaryl or PEG(2). In further embodiments, X^(n) is hydrogen,acetyl, —C(O)NH₂, HOCH₂CH₂C(O)—, diaminopropanoyl, or NH₂—(CH₂)₅—C(O)—.In another embodiment, X^(n) is hydrogen, acetyl, succinyl, glutaryl,PEG(2) or malonyl. In another embodiment, X^(n) is hydrogen, acetyl,succinyl, glutaryl, PEG(2), malonyl, methoxycarbonyl, phenylsulfonyl,3-methoxypropanoyl, ethoxycarbonyl, isobutoxycarbonyl,benzyloxycarbonyl, tert-butoxycarbonyl, 4-oxopentanoyl,2-(2-methoxyethoxy)ethoxy)acetyl, 3,4-methylenedioxyphenylacetyl,2-pyridylacetyl, phenoxyacetyl, phenylacetyl, methoxyacetyl,2-methoxyethoxycarbonyl, 2-methoxyethoxyacetyl,3-phenyl-2-hydroxypropanoyl, pent-4-ynoyl, 1-naphthylacetyl,hydroxyacetyl, 3-methoxycarbonylpropanoyl or formyl.

[0475] In certain embodiments herein, the N-terminal cap (X^(n)) isacetyl, glutaryl, or related acyl, sulfonyl or carbamoyl derivatives.Capping groups include, but are not limited to, a simple N-acetylresidue through larger fragments that impact the overall physicochemicalproperties of the conjugate. Appropriate choice of the capping groupallows delivery of either relatively hydrophilic or hydrophobicmolecules to a target site. In one embodiment, X^(n) is acetyl.

[0476] 2) X^(c) (the C-terminal Cap)

[0477] In embodiments herein where the therapeutic agent is conjugatedto the N-terminus of the peptidic substrate (i.e., where the conjugatehas formula II), the C-terminus of the peptidic substrate is acarboxylic acid or a carboxamide derivative. Appropriate choice of thecapping group allows delivery of either relatively hydrophilic orhydrophobic molecules to a target site.

[0478] In one embodiment, X^(c), together with the carbonyl group towhich it is attached, forms a carboxamide derivative of formula—C(O)NR^(d)R^(e), where R^(d) and R^(e) are selected from (i) or (ii) asfollows:

[0479] (i) R^(d) and R^(e) are each independently hydrogen, C₁-C₆-alkyl,—C₁-C₆-alkyl-OH, —C₁-C₆-alkyl-di-OH, —C₁-C₆-alkyl-tri-OH and

[0480]  provided that at least one of R^(d) and R^(e) are not hydrogenor C₁-C₆-alkyl; or

[0481] (ii) R^(d) and R^(e) together form a —CH₂CH₂OCH₂CH₂— diradical;

[0482] b is zero or an integer between 1 and 100; and

[0483] c is 0 or 1, provided that if b is zero, c is 1.

[0484] In one embodiment, R^(d) is hydrogen and R^(e) is 2-hydroxyethyl.

[0485] 2. Linkers

[0486] The conjugates optionally contain a linker (i.e., L, L¹ or L² offormulae I, II and III) that covalently binds the peptidic substrate tothe therapeutic agent. The linkers are any that result in a conjugate inwhich the peptidic portion is a substrate for a cell surface proteaseand the therapeutic agent is substantially inactive when in theconjugate and is released in active form or in a form subsequentlyactivated by the cell, tissue or environment of the targeted tissue.

[0487] For example, the linker can include of carbohydrate, peptide,diamine, arylamine, and/or hydrocarbon core structures. Linkers aredesirably synthetically accessible, provide shelf-stable products, anddo not possess any intrinsic biological activity that interferes withthe conjugates activity. They can add desirable properties such asincreasing solubility or serving to aid in trafficking the cleavedtherapeutic agent in the cell. In certain embodiments, some linkers willbe enzymatically cleaved in vitro and in vivo, and fragment to releaseactive therapeutic agent or activatable therapeutic agent. Inembodiments where the therapeutic agent is doxorubicin, the linker is,for example, a sugar and/or a peptide, such the aminosugar daunosamine.

[0488] In one embodiment, linkers for use herein include, but are notlimited to, a biscarbonyl alkyl diradical whereby an amine moiety on thetherapeutic agent is connected with the linker unit to form an amidebond and the amino terminus of the peptidic substrate is connected withthe other end of the linker unit also forming an amide bond. Conversely,a diaminoalkyl diradical linker unit, whereby a carbonyl moiety on thecytotoxic agent is covalently attached to one of the amines of thelinker unit while the other amine of the linker unit is covalentlyattached to the C-terminus of the peptidic substrate, also can beuseful. Other such linker units which are stable to the physiologicalenvironment when not in the presence of a cell surface protease, but arecleavable upon the cleavage of the cell surface protease proteolyticcleavage site, are intended for use herein. Furthermore, linker unitscan be utilized that, upon cleavage of the cell surface proteaseproteolytic cleavage site, remain attached to the therapeutic agent butdo not significantly decrease the therapeutic activity of such apost-cleavage therapeutic agent derivative when compared with anunmodified therapeutic agent.

[0489] In other embodiments, the linker is a diamine containing a cyclicalkyl moiety and, in certain embodiments, the diamine contains abicycloalkylene moiety. Examples of such diamine linkers include, butare not limited to, 1,4-bis(aminomethyl)cyclohexane,1,4-bis(aminomethyl)-cycloheptane, 1,3-bis(aminomethyl)cyclopentane,1-amino-4-(aminomethyl)cyclohexane, 1,4-diaminocyclohexane and1,4-bis(aminomethyl)-bicyclo[2.2.2]octane.

[0490] Other linkers include 1,ω-diaminoalkanes, including, but notlimited to, 1,3-diaminopropane, and 1,ω-dicarbonylalkanes, including,but not limited to, oxalic, malonic, succinic, glutaric, adipic andpivalic acids.

[0491] Further linkers for use in the conjugates provided herein includeself-eliminating linkers such as those of the following formulae:

[0492] where A is NH or 0; D is N(H or alkyl) or 0; R²⁵ is H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substitutedwith 1 or more, such as 1 to 3, substituents selected from halo, haloalkyl and alkyl, aralkyl, heteroaralkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, alk(en)(yn)ylgroups, halo, pseudohalo, cyano, hydroxy, haloalkyl and polyhaloalkyl,such as, for example, halo lower alkyl, especially trifluoromethyl,formyl, alkylcarbonyl, arylcarbonyl that optionally is substituted with1 or more, such as, for example, 1 to 3, substituents selected from, forexample, halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy,alkoxycarbonyl, aryloxycarbonyl, aminoimino, alkoxycarbonylamino,aryloxycarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy,alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino,alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro,mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano,isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl andarylamino-sulfonyl.; and y is an integer from 1 to 3.

[0493] 3. Therapeutic Agents

[0494] The conjugates are intended for modifying a variety of biologicalresponses. Accordingly, the therapeutic agents are any agents, includingproteins and polypeptides, small molecules and other molecules thatpossess or potentiate a desired biological activity. Such moleculesinclude cytotoxic agents, such as, but are not limited to, a toxin suchas abrin, ricin A, pseudomonas exotoxin, shiga toxin, diphtheria toxinand other such toxins and toxic portions and/or subunits or chainsthereof; proteins such as, but not limited to, tumor necrosis factor,α-interferon, γ-interferon, nerve growth factor, platelet derived growthfactor, tissue plasminogen activator; or, biological response modifierssuch as, for example, lymphokines, interleukin-I (IL-1), interleukin-2(IL-2), interleukin-6 (IL-6), granulocyte macrophage colony stimulatingfactor (GMCSF), granulocyte colony stimulating factor (G-CSF),erythropoietin (EPO), pro-coagulants such as tissue factor and tissuefactor variants, pro-apoptotic agents such FAS-ligand, fibroblast growthfactors (FGF), nerve growth factor and other growth factors. Each mustbe in a form that can enter a cell or otherwise exert a therapeuticeffect when in the vicinity thereof.

[0495] Thus, therapeutic agents, include, but are not limited to,anti-tumor, anti-angiogenic, pro-apoptotic, anti-cancer and anti-mitoticagents. These are conjugated, optionally via a linker, to a substrate,such as peptidic substrate, which is a substrate for the protease.

[0496] Among the therapeutic agents are cytotoxic agents that include,in general, but are not limited to, alkylating agents, toxins,antiproliferative agents and tubulin binding agents. Classes ofcytotoxic agents for use herein include, for example, the anthracyclinefamily of drugs, the vinca drugs, the mitomycins, the bleomycins, thecytotoxic nucleosides, the pteridine family of drugs, diynenes, themaytansinoids, the epothilones, the taxanes and the podophyllotoxins.

[0497] Exemplary members of those classes include, for example,doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate,methopterin, dichloro-methotrexate, mitomycin C, porfiromycin,5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, podophyllotoxin,or podophyllotoxin derivatives such as etoposide or etoposide phosphate,melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine,maytansinol, epothilone A or B, taxotere, taxol and the like. Other suchtherapeutic agents include estramustine, cisplatin, combretastatin andanalogs, and cyclophosphamide. One skilled in the art can make chemicalmodifications to the desired therapeutic agent in order to makereactions of that compound more convenient for purposes of preparing theconjugates.

[0498] Particular therapeutic agents include the following drugs. Oneskilled in the art understands that these structural formulae areexemplary only and that such compounds or derivatives or analogs thereofhave acquired in the art different generic or trivial names.

[0499] a. The Methotrexate Group of Formula (1):

[0500] in which

[0501] R¹² is amino or hydroxy;

[0502] R⁷ is hydrogen or methyl;

[0503] R⁸ is hydrogen, fluoro, chloro, bromo or iodo;

[0504] R⁹ is hydroxy or a moiety which completes a salt of thecarboxylic acid.

[0505] b. The Mitomycin Group of Formula (2):

[0506] in which R¹⁰ is hydrogen or methyl.

[0507] c. The Bleomycin Group of Formula (3):

[0508] in which R¹¹ is hydroxy, amino, C₁-C₃ alkylamino, di(C₁-C₃alkyl)amino, C₄-C₆ polymethylene amino, —NHCH₂CH₂CH₂CH₂NH—C(NH)NH₂ or—NHCH₂CH₂CH₂S⁺(CH₃)₂.

[0509] d. Melphalan of Formula (4):

[0510] e. Mercaptopurine of Formula (5):

[0511] f. Cyotosine Arabinoside of Formula (6):

[0512] g. Podophyllotoxins of Formula (7):

[0513] in which

[0514] R¹³ is hydrogen or methyl; and

[0515] R¹⁴ is methyl or thienyl or a phosphate salt thereof.

[0516] h. The Vinca Alkaloid Group of Drugs of Formula (8):

[0517] in which

[0518] when R¹⁷ and R¹⁸ are taken singly, R¹⁵ is H, CH₃ or CHO; and

[0519] R¹⁸ is H, and one of R¹⁶ and R¹⁷ is ethyl and the other is H orOH;

[0520] when R¹⁷ and R¹⁸ are taken together with the carbons to whichthey are attached, they form an oxirane ring in which case R¹⁶ is ethyl;and

[0521] R¹⁹ is hydrogen, (C₁-C₃ alkyl)-CO, or chlorosubstituted (C₁-C₃alkyl)-CO.

[0522] The conjugates provided herein where the therapeutic agent is thevinca alkaloid vinblastine include those of formula:

[0523] where the peptidic substrate is as described above for formulae Iand II; L is a linker such as —NH—(CH₂)_(u)—T—(CH₂)_(u)—NH—; X^(n) is

[0524] a) hydrogen,

[0525] b) —(C═O)R^(1a),

[0526] c)

[0527] d)

[0528] e)

[0529] f) ethoxysquarate; and

[0530] g) cotininyl;

[0531] R¹ and R² are independently hydrogen, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ aralkyl and aryl;

[0532] R^(1a) is C₁-C₆-alkyl, hydroxylated C₃-C₈-cycloalkyl,polyhydroxylated C₃-C₈-cycloalkyl, hydroxylated aryl, polyhydroxylatedaryl or aryl,

[0533] R¹⁹ is hydrogen, (C₁-C₃ alkyl)-CO, or chlorosubstituted (C₁-C₃alkyl)-CO;

[0534] T is selected from cyclopentyl, cyclohexyl, cycloheptyl orbicyclo[2.2.2]octanyl;

[0535] a is 1, 2, 3 or 4;

[0536] b is zero or an integer between 1 and 100;

[0537] c is 0 or 1, provided that if b is zero, c is 1;

[0538] g is 1, 2 or 3;

[0539] u is 0, 1, 2 or 3;

[0540] or a pharmaceutically acceptable derivative thereof.

[0541] i. Difluoronucleosides of Formula (9):

[0542] in which R²¹ is a base of one of the formulae:

[0543] R²² is hydrogen, methyl, bromo, fluoro, chloro or iodo;

[0544] R²³ is —OH or —NH2;

[0545] R²⁴ is hydrogen, bromo, chloro or lodo.

[0546] j. Estramustine (10):

[0547] k. Cyclophosphamide (11):

[0548] I. Anthracycline Antibiotics of Formula (12):

[0549] in which

[0550] R^(a) is —CH₃, —CH₂OH, —CH₂OCO(CH₂)₃CH₃, or —CH₂OCOCH(OC₂H₅)₂;

[0551] R^(b) is —OCH₃, —OH or —H;

[0552] R^(c) is —NH₂, —NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl,1-piperidinyl, 4-methoxy-1-piperidinyl, benzylamine, dibenzylamine,cyanomethylamine, or 1-cyano-2-methoxyethyl amine;

[0553] R⁵ is —OH —OTHP or —H; and

[0554] R⁶ is —OH or —H provided that R6 is not —OH when R⁵ is —OH or—OTHP.

[0555] Table 2, which follows, provides a number of anthracycline drugsand their generic or trivial names:

Compound R^(a) R^(b) R^(c) R⁵ R⁶ daunorubicin^(a) CH₃ OCH₃ NH₂ OH Hdoxorubicin^(b) CH₂OH OCH₃ NH₂ OH H detorubicin CH₂OCOCH(OC₂H₅)₂ OCH₃NH₂ OH H carminomycin CH₃ OH NH₂ OH H idarubicin CH₃ H NH₂ OH Hepirubicin CH₂OH OCH₃ NH₂ OH OH esorubicin CH₂OH OCH₃ NH₂ H H THP CH₂OHOCH₃ NH₂ OTHP H AD-32 CH₂OCO(CH₂)₃CH₃ OCH₃ NHCOCF₃ OH H

[0556] In one embodiment, when the therapeutic agent is doxorubicin, itis conjugated to the peptidic substrate via the amino group of theaminoglycoside moiety of doxorubicin.

[0557] m. Maytansinol

[0558] where R is PhC(O) or t-BuOC(O).

[0559] In one embodiment, when the therapeutic agent is taxol(R=C(O)Ph), the peptidic substrate is conjugated to the secondaryhydroxyl group of the cyclohexane moiety of taxol.

[0560] p. Ribosome-Inactivating Proteins

[0561] Ribosome-inactivating proteins (RIPs), which include ricin, abrinand saporin, are plant proteins that catalytically inactivate eukaryoticribosomes. RIPS inactivate ribosomes by interfering with the proteinelongation step of protein synthesis. For example, the RIP saporin(hereinafter also referred to as SAP) has been shown to enzymaticallyinactivate 60S ribosomes by cleavage of the n-glycosidic bond of theadenine at position 4324 in the rat 28S ribosomal RNA (rRNA). Some RIPs,such as the toxins abrin and ricin, contain two constituent chains: acell-binding chain that mediates binding to cell surface receptors andinternalization of the molecule; and an enzymatically active chainresponsible for protein synthesis inhibitory activity. Such RIPs aretype II RIPs. Other RIPs, such as the saporins, are single chains andare designated type I RIPs. Because such RIPs lack a cell-binding chain,they are less toxic to whole cells than the RIPs that have two chains.Two chain RIPs are generally used for conjugation herein, unless asingle chain is further conjugated to an agent, such as a growth factorthat mediates binding and internalization.

[0562] Several structurally related RIP's have been isolated from seedsand leaves of the plant Saponaria officinalis (soapwort). Among these,SAP-6 is the most active and abundant, representing 7% of total seedproteins. Saporin is very stable, has a high isoelectric point, does notcontain carbohydrates, and is resistant to denaturing agents, such assodium dodecyl sulfate (SDS), and a variety of proteases. The amino acidsequences of several saporin-6 isoforms from seeds are known and thereappear to be families of saporin RIPs differing in a few amino acidresidues. Because saporin is a type I RIP, it does not possess acell-binding chain. Consequently, its toxicity to whole cells is muchlower than the other toxins, such as ricin and abrin. When internalizedby eukaryotic cells, however, its cytotoxicity is 100- to 1000-fold morepotent than ricin A chain.

[0563] 4. Exemplary Conjugates

[0564] The conjugates provided herein, are prepared by identifyingsuitable peptidic substrates for the targeted cell surface protease, ora soluble, shed or released form thereof, and forming a conjugate of thepeptidic substrate(s) with a therapeutic agent(s). Exemplary conjugates,containing peptidic substrates designed, for example, for cleavage byMTSP1, endotheliase 1 and urokinase, are described. It is understoodthat upon identification of a cell surface protease, includingcell-associated and cell-localized proteases, or a soluble, shed orreleased form thereof, in or associated with a cell involved in adisease or other conditions of interest, or with a cell present in thevicinity of a cell or tissue involved in or associated with a disease orother condition of interest, suitable peptidic substrates therefor canbe empirically designed and then conjugated to therapeutic agents asexemplified herein.

[0565] In certain embodiments, the conjugates for use in thecompositions and methods provided herein include:

[0566] Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 46);

[0567] Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 47);

[0568] Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 48);

[0569] Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 49);

[0570] Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ IDNO: 50);

[0571] Ac-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO:51);

[0572] Ac-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 52);

[0573] Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 53);

[0574] Ac-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:54);

[0575] Ac-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 55);

[0576] Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ IDNO: 56);

[0577] Ac-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO:57);

[0578] Ac-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 58);

[0579] Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 59);

[0580] Ac-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:60); and

[0581] Ac-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 61).

[0582] In further embodiments herein, the conjugates areAc-Leu-Arg-Ala-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 62);Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 63);Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 64);and Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:65).

[0583] In other embodiments herein, the conjugates are

[0584] Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ IDNO: 66);

[0585] Ac-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO:67);

[0586] Ac-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 68);

[0587] Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 69);

[0588] Ac-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:70);

[0589] Ac-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 71);

[0590] Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ IDNO: 72);

[0591] Ac-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO:73);

[0592] Ac-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 74);

[0593] Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 75);

[0594] Ac-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:76); and

[0595] Ac-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 77).

[0596] In other embodiments, the conjugates for use herein include thefollowing:

[0597] pyroGlu-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 78);

[0598] CH₃SO₂-D-HHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 79);

[0599] N-p-tosyl-Gly-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:80);

[0600] Benzoyl-Val-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 81);

[0601] CH₃SO₂-D-HHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 82);

[0602] N-α-Z-D-Arg-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 83)(Z=benzyloxycarbonyl);

[0603] pyroGlu-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 84);

[0604] H-D-Ile-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 85);Cbo-L-(γ)Glu(α-t-BuO)-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:86) (Cbo=carbobenzoxy);

[0605] H-D-Pro-Phe-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 87);

[0606] H-D-Val-Leu-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 88);

[0607] Bz-Ile-Glu(γ-OH)-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:89) (Bz=benzoyl);

[0608] Bz-Ile-Glu(γ-OMe)-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:90);

[0609] Benzoyl-Pro-Phe-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 91);

[0610] H-D-Phe-Pip-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 92);

[0611] H-D-Val-Leu-Lys-Ala-Ala-(therapeutic agent) (SEQ ID NO: 93);

[0612] H-D-Nle-HHT-Lys-Ala-Ala-(therapeutic agent) (SEQ ID NO: 94);

[0613] Pyr-Arg-Thr-Lys-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 95);

[0614] H-Arg-Gln-Arg-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 96);

[0615] Boc-Gln-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 97);

[0616] Z-Arg-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 98);

[0617] H-D-HHT-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 99);

[0618] H-D-CHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 100);

[0619] MeSO₂-dPhe-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 101);

[0620] δ-Z-D-Lys-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 102);and

[0621] CH₃SO₂-D-CHA-But-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:103).

[0622] In another embodiment, the conjugates for use in the compositionsand methods provided herein include:

[0623] Ac-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 104);

[0624] Ac-Arg-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO:105);

[0625] Ac-Leu-Arg-Arg-Gin-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ IDNO: 106);

[0626] Ac-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO: 107);

[0627] Ac-Arg-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO: 108);

[0628] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Gly-Gly-(therapeutic agent) (SEQ IDNO: 109);

[0629] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO:110);

[0630] Ac-Arg-Arg-Gln-Ser-Arg-Ile-(therapeutic agent) (SEQ ID NO: 111);and

[0631] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-Ile-(therapeutic agent) (SEQ IDNO: 112).

[0632] In certain embodiments, the conjugates for use in thecompositions and methods provided herein include:

[0633] Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 113);

[0634] Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Leu-(therapeutic,agent) (SEQ IDNO: 114);

[0635] Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 115);

[0636] Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 116);

[0637] Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ IDNO: 117);

[0638] Ac-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO:118);

[0639] Ac-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO: 119);

[0640] Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 120);

[0641] Ac-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:121);

[0642] Ac-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 122);

[0643] Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 123);

[0644] Ac-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:124);

[0645] Ac-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 125);

[0646] Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 126);

[0647] Ac-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:127); and

[0648] Ac-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 128).

[0649] In further embodiments herein, the conjugates areAc-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:129); Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 130); Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQID NO: 131); and Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Leu-(therapeutic agent)(SEQ ID NO: 132).

[0650] In other embodiments herein, the conjugates are

[0651] Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ IDNO: 133);

[0652] Ac-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO:134);

[0653] Ac-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO: 135);

[0654] Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 136);

[0655] Ac-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:137);

[0656] Ac-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 138);

[0657] Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 139);

[0658] Ac-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:140);

[0659] Ac-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 141);

[0660] Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 142);

[0661] Ac-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:143); and

[0662] Ac-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 144).

[0663] In other embodiments, the conjugates for use herein include thefollowing:

[0664] pyroGlu-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 145);CH₃SO₂-D-HHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 146);

[0665] N-p-tosyl-Gly-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:147);

[0666] Benzoyl-Val-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 148);

[0667] CH₃SO₂-D-HHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:149);

[0668] N-α-Z-D-Arg-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 150)(Z=benzyloxycarbonyl);

[0669] pyroGlu-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 151);

[0670] H-D-Ile-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 152);

[0671] Cbo-L-(γ)Glu(α-t-BuO)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 153) (Cbo=carbobenzoxy);

[0672] H-D-Pro-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 154);

[0673] H-D-Val-Leu-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 155);

[0674] Bz-Ile-Glu(γ-OH)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:156) (Bz=benzoyl);

[0675] Bz-Ile-Glu(γ-OMe)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:157);

[0676] Benzoyl-Pro-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 158);

[0677] H-D-Phe-Pip-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 159);

[0678] H-D-Val-Leu-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO: 160);

[0679] H-D-Nle-HHT-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO: 161);

[0680] Pyr-Arg-Thr-Lys-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 162);

[0681] H-Arg-Gln-Arg-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 163);

[0682] Boc-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 164);

[0683] Z-Arg-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 165);

[0684] H-D-HHT-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 166);

[0685] H-D-CHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 167);

[0686] MeSO₂-dPhe-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 168);

[0687] δ-Z-D-Lys-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 169);and

[0688] CH₃SO₂-D-CHA-But-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:170).

[0689] In another embodiment, the conjugates for use in the compositionsand methods provided herein include:

[0690] Ac-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 171);

[0691] Ac-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:172);

[0692] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 173);

[0693] Ac-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 174);

[0694] Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 175);

[0695] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 176);

[0696] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO:177);

[0697] Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 178);and

[0698] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 179).

[0699] In other embodiments, the conjugates provided herein include:

[0700] Ac-Arg-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 180);

[0701] Ac-Arg-Gln-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 181);

[0702] Ac-Arg-Gln-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 182);

[0703] Ac-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 183);

[0704] Ac-Arg-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 184);

[0705] Ac-Arg-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 185);

[0706] Ac-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 186);

[0707] Ac-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 187);

[0708] Ac-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 188);

[0709] Ac-Gln-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 189); and

[0710] Ac-Gln-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 190).

[0711] In further embodiments, the conjugates for use in thecompositions and methods provided herein include:

[0712] Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 191);

[0713] Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 192);

[0714] Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 193);

[0715] Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 194);

[0716] Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 195);

[0717] Ac-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 196);

[0718] Ac-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:197);

[0719] Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 198);

[0720] Ac-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 199);

[0721] Ac-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:200);

[0722] Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 201);

[0723] Ac-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 202);

[0724] Ac-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:203);

[0725] Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 204);

[0726] Ac-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 205); and

[0727] Ac-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:206).

[0728] In further embodiments herein, the conjugates areAc-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:207); Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 208); Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent)(SEQ ID NO: 209); andAc-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:210).

[0729] In other embodiments herein, the conjugates are

[0730] Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 211);

[0731] Ac-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 212);

[0732] Ac-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:213);

[0733] Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 214);

[0734] Ac-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 215);

[0735] Ac-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:216);

[0736] Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 217);

[0737] Ac-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 218);

[0738] Ac-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:219);

[0739] Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 220);

[0740] Ac-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 221); and

[0741] Ac-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:222).

[0742] In other embodiments, the conjugates for use herein include thefollowing:

[0743] pyroGlu-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 223);

[0744] CH₃SO₂-D-HHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:224);

[0745] N-p-tosyl-Gly-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:225); Benzoyl-Val-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:226); CH₃SO₂-D-HHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:227);

[0746] N-α-Z-D-Arg-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:228) (Z=benzyloxycarbonyl);

[0747] pyroGlu-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 229);

[0748] H-D-Ile-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 230);

[0749] Cbo-L-(γ)Glu(α-t-BuO)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent)(SEQ ID NO: 231) (Cbo=carbobenzoxy);

[0750] H-D-Pro-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 232);

[0751] H-D-Val-Leu-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 233);

[0752] Bz-Ile-Glu(γ-OH)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 234) (Bz=benzoyl);

[0753] Bz-Ile-Glu(γ-OMe)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 235);

[0754] Benzoyl-Pro-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:236);

[0755] H-D-Phe-Pip-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 237);

[0756] H-D-Val-Leu-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 238);

[0757] H-D-Nle-HHT-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 239);

[0758] Pyr-Arg-Thr-Lys-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:240);

[0759] H-Arg-Gln-Arg-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:241);

[0760] Boc-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 242);

[0761] Z-Arg-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 243);

[0762] H-D-HHT-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 244);

[0763] H-D-CHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 245);

[0764] MeSO₂-dPhe-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:246);

[0765] δ-Z-D-Lys-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:247); and

[0766] CH₃SO₂-D-CHA-But-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:248).

[0767] In another embodiment, the conjugates for use in the compositionsand methods provided herein include:

[0768] Ac-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:249);

[0769] Ac-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 250);

[0770] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 251);

[0771] Ac-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 252);

[0772] Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 253);

[0773] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 254);

[0774] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 255);

[0775] Ac-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:256); and

[0776] Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 257).

[0777] In other embodiments, the conjugates provided herein include:

[0778] Ac-Arg-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:258);

[0779] Ac-Arg-Gln-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:259);

[0780] Ac-Arg-Gln-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:260);

[0781] Ac-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 261);

[0782] Ac-Arg-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 262);

[0783] Ac-Arg-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 263);

[0784] Ac-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 264);

[0785] Ac-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 265);

[0786] Ac-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 266);

[0787] Ac-Gln-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 267);and

[0788] Ac-Gln-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 268).

[0789] In another embodiment, the conjugates provided herein include:

[0790] Ac-Gly-dSer-Ala-Arg-Ser-Ala-(therapeutic agent) (SEQ ID NO: 569);

[0791] Ac-Arg-Gly-dSer-Ala-Arg-Ser-Ala-(therapeutic agent) (SEQ ID NO:570);

[0792] Ac-Gly-Ser-Gly-Arg-Ser-Ala-(therapetutic agent) (SEQ ID NO: 571);

[0793] Ac-Arg-Gly-Ser-Gly-Arg-Ser-Ala-(therapetutic agent) (SEQ ID NO:572);

[0794] Ac-Leu-Arg-Gly-Ser-Gly-Arg-Ser-Ala-(therapetutic agent) (SEQ IDNO: 573);

[0795] Ac-Leu-Arg-Gly-dSer-Ala-Arg-Ser-Ala-(therapetutic agent) (SEQ IDNO: 574);

[0796] Ac-Cys(Me)-Pro-Gly-Arg-Val-Val-(therapeutic agent) (SEQ ID NO:575);

[0797] Ac-Arg-Cys(Me)-Pro-Gly-Arg-Val-Val-(therapeutic agent) (SEQ IDNO: 577);

[0798] Ac-Arg-Arg-Cys(Me)-Pro-Gly-Arg-Val-Val-(therapeutic agent) (SEQID NO: 578);

[0799] Ac-Val-Ser-Ala-Arg-Met-Ala-(therapeutic agent) (SEQ ID NO: 579);

[0800] Ac-Ile-Val-Ser-Ala-Arg-Met-Ala-(therapeutic agent) (SEQ ID NO:580);

[0801] Ac-Val-Ile-Val-Ser-Ala-Arg-Met-Ala-(therapeutic agent) (SEQ IDNO: 581);

[0802] Ac-Val-Ile-Val-Ser-Ala-Arg-nLeu-Ala-(therapeutic agent) (SEQ IDNO: 582);

[0803] Ac-Val-Ser-Ala-Arg-nLeu-Ala-(therapeutic agent) (SEQ ID NO: 583);

[0804] Ac-Ile-Val-Ser-Ala-Arg-nLeu-Ala-(therapeutic agent) (SEQ ID NO:584);

[0805] Ac-Gly-Ser-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 585);

[0806] Ac-Gly-Ser-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:586);

[0807] Ac-Gly-Ser-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 587);

[0808] Ac-Ser-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 588);

[0809] Ac-Ser-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 589);

[0810] Ac-Ser-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 590);

[0811] Ac-Arg-Gly-Ser-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:591);

[0812] Ac-Arg-Gly-Ser-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 592);

[0813] Ac-Arg-Gly-Ser-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:593);

[0814] Ac-Leu-Arg-Gly-Ser-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 594);

[0815] Ac-Leu-Arg-Gly-Ser-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 595); and

[0816] Ac-Leu-Arg-Gly-Ser-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 596).

[0817] In another embodiment, the conjugates provided herein areselected from:

[0818] Ac-R-Q-G-R-S-L-(therapeutic agent) (SEQ ID NO: 491);

[0819] Ac-R-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 492);

[0820] Ac-R-Q-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 493);

[0821] Ac-R-Q-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 494);

[0822] Ac-R-Q-G-R-S-F-(therapeutic agent) (SEQ ID NO: 495);

[0823] Ac-R-Q-G-R-A-L-(therapeutic agent) (SEQ ID NO: 496);

[0824] Ac-R-Q-G-R-A-L-(therapeutic agent) (SEQ ID NO: 497);

[0825] Ac-R-Q-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 498);

[0826] Ac-R-Q-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 499);

[0827] Ac-R-Q-G-R-A-nV-(therapeutic agent) (SEQ ID NO: 500);

[0828] Ac-R-Q-G-R-A-Cha-(therapeutic agent) (SEQ ID NO: 501);

[0829] Ac-R-Q-G-R-A-F-(therapeutic agent) (SEQ ID NO: 502);

[0830] Ac-R-N-G-R-S-L-(therapeutic agent) (SEQ ID NO: 503);

[0831] Ac-R-N-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 504);

[0832] Ac-R-Q-A-R-S-L-(therapeutic agent) (SEQ ID NO: 505);

[0833] Ac-R-Q-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 506);

[0834] Ac-R-Q-A-R-S-nV-(therapeutic agent) (SEQ ID NO: 507);

[0835] Ac-R-Q-A-A-S-Cha-(therapeutic agent) (SEQ ID NO: 508);

[0836] Ac-R-Q-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 509);

[0837] Ac-R-Q-A-R-T-nL-(therapeutic agent) (SEQ ID NO: 510);

[0838] Ac-R-Q-A-R-A-L-(therapeutic agent) (SEQ ID NO: 511);

[0839] Ac-R-Q-A-R-A-nL-(therapeutic agent) (SEQ ID NO: 512);

[0840] Ac-R-Q-A-R-A-nV-(therapeutic agent) (SEQ ID NO: 513);

[0841] Ac-R-Q-A-R-A-Cha-(therapeutic agent) (SEQ ID NO: 514);

[0842] Ac-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 515);

[0843] Ac-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO: 516);

[0844] Ac-R-Q-S-R-A-nL-(therapeutic agent) (SEQ ID NO: 517);

[0845] Ac-R-Q-S-R-A-L-(therapeutic agent) (SEQ ID NO: 518);

[0846] Ac-R-Q-S-R-A-nV-(therapeutic agent) (SEQ ID NO: 519);

[0847] Ac-R-Q-S-R-A-Cha-(therapeutic agent) (SEQ ID NO: 520);

[0848] Ac-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 521);

[0849] Ac-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 522);

[0850] Ac-R-Q-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 523);

[0851] Ac-R-Q-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 524);

[0852] Ac-R-Q-S-R-S-nV-(therapeutic agent) (SEQ ID NO: 525);

[0853] Ac-R-Q-S-R-S-allylG-(therapeutic agent) (SEQ ID NO: 526);

[0854] Ac-R-Q-S-R-S-Cha-(therapeutic agent) (SEQ ID NO: 527);

[0855] Ac-R-Q-S-R-T-nL-(therapeutic agent) (SEQ ID NO: 528);

[0856] Ac-R-Q-T-R-S-S-L-(therapeutic agent) (SEQ ID NO: 529);

[0857] Ac-R-Q-T-R-S-L-(therapeutic agent) (SEQ ID NO: 530);

[0858] Ac-R-N-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 531);

[0859] Ac-R-Q-F-R-S-L-(therapeutic agent) (SEQ ID NO: 532);

[0860] Ac-R-Q-F-R-S-nL-(therapeutic agent) (SEQ ID NO: 534);

[0861] Ac-R-Q-F-R-S-nV-(therapeutic agent) (SEQ ID NO: 535);

[0862] Ac-R-Q-F-R-S-nL-(therapeutic agent) (SEQ ID NO: 536);

[0863] Ac-R-Q-F-R-S-Cha-(therapeutic agent) (SEQ ID NO: 537);

[0864] Ac-R-Q-F-R-A-L-(therapeutic agent) (SEQ ID NO: 538);

[0865] Ac-R-Q-F-R-A-nL-(therapeutic agent) (SEQ ID NO: 539);

[0866] Ac-R-Q-F-R-A-nV-(therapeutic agent) (SEQ ID NO: 540);

[0867] Ac-R-Q-F-R-A-Cha-(therapeutic agent) (SEQ ID NO: 541);

[0868] Ac-Q-S-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 542);

[0869] MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO: 483);

[0870] MeOCO-Quat3-G-R-S-L-(therapeutic agent) (SEQ ID NO: 484);

[0871] MeOCO-Quat-G-R-S-L-(therapeutic agent) (SEQ ID NO: 485);

[0872] MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO: 486);

[0873] MeOCO-Quat5-G-R-S-L-(therapeutic agent) (SEQ ID NO: 487);

[0874] MeOCO-Quat2-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 488);

[0875] MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO: 489);

[0876] MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO: 490);

[0877] Ac-Q-G-R-S-L-(therapeutic agent) (SEQ ID NO: 445);

[0878] Ac-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 446);

[0879] Ac-Q-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 447);

[0880] Ac-N-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 448);

[0881] Ac-Q-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 449);

[0882] Ac-Q-G-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 450);

[0883] Ac-Q-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 451);

[0884] Ac-Q-G-R-S-S-allylG-(therapeutic agent) (SEQ ID NO: 452);

[0885] Ac-Q-G-R-S-S-allylG-(therapeutic agent) (SEQ ID NO: 453);

[0886] Ac-Q-A-R-S-L-(therapeutic agent) (SEQ ID NO: 454);

[0887] Ac-Q-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 455);

[0888] Ac-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 456);

[0889] Ac-Q-S-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 457);

[0890] Ac-Q-S-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 458);

[0891] Ac-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 459);

[0892] Ac-Q-T-R-S-S-L-(therapeutic agent) (SEQ ID NO: 460);

[0893] Ac-Q-Aib-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 461);

[0894] Ac-Q-Aib-R-S-S-L-(therapeutic agent) (SEQ ID NO: 462);

[0895] Ac-Q-Abu-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 463);

[0896] Ac-Q-Abu-R-S-S-L-(therapeutic agent) (SEQ ID NO: 464);

[0897] Ac-Q-Cha-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 465);

[0898] Ac-Q-F-R-S-L-(therapeutic agent) (SEQ ID NO: 466);

[0899] Ac-Q-F-R-S-S-L-(therapeutic agent) (SEQ ID NO: 467);

[0900] Ac-Q-Y-R-S-S-L-(therapeutic agent) (SEQ ID NO: 468);

[0901] Ac-R-G-R-S-L-(therapeutic agent) (SEQ ID NO: 469);

[0902] Ac-R-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 470);

[0903] Ac-R-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 471);

[0904] Ac-R-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 472);

[0905] Ac-R-A-R-S-L-(therapeutic agent) (SEQ ID NO: 473);

[0906] Ac-R-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 474);

[0907] Ac-R-S-R-S-L-(therapeutic agent) (SEQ ID NO: 475);

[0908] Ac-R-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 476);

[0909] Ac-R-S-R-S-Cha-(therapeutic agent) (SEQ ID NO: 477);

[0910] Ac-R-S-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 478);

[0911] Ac-R-F-R-S-L-(therapeutic agent) (SEQ ID NO: 479);

[0912] Ac-R-F-R-S-Cha-(therapeutic agent) (SEQ ID NO: 480);

[0913] Ac-Y-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 481);

[0914] Ac-M(O2)-S-R-S-L-(therapeutic agent) (SEQ ID NO: 482);

[0915] Ac-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 105);

[0916] Ac-R-R-Q-S-R-I-(therapeutic agent) (SEQ ID NO: 610);

[0917] Ac-R-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 543);

[0918] Ac-R-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 544);

[0919] Ac-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 545);

[0920] Ac-R-G-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 546);

[0921] Ac-R-G-S-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 547);

[0922] Ac-R-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 548);

[0923] Ac-I-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 549);

[0924] Ac-R-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO: 108);

[0925] Ac-R-R-Q-S-R-I-(therapeutic agent) (SEQ ID NO: 111);

[0926] Ac-L-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 106);

[0927] Ac-L-R-R-Q-S-R-G-G-(therapeutic agent) (SEQ ID NO: 109);

[0928] Ac-L-R-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO: 110);

[0929] Ac-L-R-R-Q-S-R-A-I-(therapeutic agent) (SEQ ID NO: 112);

[0930] Ac-L-R-R-Q-S-R-A-I-(therapeutic agent) (SEQ ID NO: 611);

[0931] Ac-L-R-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 550); and

[0932] Ac-L-R-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 551);

[0933] In another embodiment, the conjugates provided herein areselected from:

[0934] Ac-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 362);

[0935] Ac-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 363);

[0936] Ac-S-G-R-S-S-S-L-(therapeutic agent) (SEQ ID NO: 364);

[0937] Ac-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 365);

[0938] Ac-S-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 366); isomer 1

[0939] Ac-S-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 367); isomer 2

[0940] Ac-S-G-R-S-G(hex)-(therapeutic agent) (SEQ ID NO: 368);

[0941] Ac-S-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 369);

[0942] Ac-S-G-R-S-hCha-(therapeutic agent) (SEQ ID NO: 370);

[0943] Ac-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 371);

[0944] Ac-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 372);

[0945] Ac-S-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 373);

[0946] Ac-T-G-R-S-Abu-(therapeutic agent) (SEQ ID NO: 374);

[0947] Ac-T-G-R-S-L-(therapeutic agent) (SEQ ID NO: 375);

[0948] Ac-T-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 376);

[0949] Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 377);

[0950] Ac-T-G-R-S-G(hex)-(therapeutic agent) (SEQ ID NO: 378);

[0951] Ac-T-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 379);

[0952] Ac-T-G-R-S-hCha-(therapeutic agent) (SEQ ID NO: 380);

[0953] Ac-T-G-R-T-Abu-(therapeutic agent) (SEQ ID NO: 381);

[0954] Ac-T-G-R-hS-nL-(therapeutic agent) (SEQ ID NO: 382);

[0955] Ac-T-G-R-Abu-nL-(therapeutic agent) (SEQ ID NO: 383);

[0956] Ac-T-G-R-Abu-nV-(therapeutic agent) (SEQ ID NO: 384);

[0957] Ac-T-G-F(Gn)-S-nL-(therapeutic agent) (SEQ ID NO: 385);

[0958] Ac-T-G-F(Gn)-S-Cha-(therapeutic agent) (SEQ ID NO: 386);

[0959] Ac-T-G-F(Gn)-Abu-nV-(therapeutic agent) (SEQ ID NO: 387);

[0960] Ac-T-G-K(alloc)-S-nL-(therapeutic agent) (SEQ ID NO: 388);

[0961] Ac-T-G-K-S-nL-(therapeutic agent) (SEQ ID NO: 389);

[0962] Ac-T-G-hR-S-nL-(therapeutic agent) (SEQ ID NO: 390);

[0963] Ac-(hS)G-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 391);

[0964] MeOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 392);

[0965] PhSO2-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 393);

[0966] MeOEtCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 394);

[0967] MeO(EtO)2Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 395);

[0968] 4-oxo-Pentanoyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 396);

[0969] 3,4-MethyidioxyPhAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO:397);

[0970] 2-PyridylAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 398);

[0971] PhOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 399);

[0972] L-3-PhLactyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 400);

[0973] MeOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 401);

[0974] PhAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 402);

[0975] MeOEtOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 403);

[0976] MeOEtOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 404);

[0977] HOOCButa-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 405);

[0978] Z-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 406);

[0979] EtOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 407);

[0980] βA-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 408);

[0981] Pent-4-ynoyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 409);

[0982] NapAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 410);

[0983] iBoc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 411);

[0984] HOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 412);

[0985] MeSucc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 413);

[0986] N,N-diMeGly-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 414);

[0987] Succ-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 415);

[0988] HCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 416);

[0989] Ac-T-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 417);

[0990] Ac-T-A-F(Gn)-S-nL-(therapeutic agent) (SEQ ID NO: 418);

[0991] Ac-T-A-R-Abu-nV-(therapeutic agent) (SEQ ID NO: 419);

[0992] Ac-T-A-R-S-Abu-(therapeutic agent) (SEQ ID NO: 420);

[0993] Ac-T-A-R-T-Abu-(therapeutic agent) (SEQ ID NO: 421);

[0994] Ac-T-S(O-Me)-R-S-nL-(therapeutic agent) (SEQ ID NO: 422);

[0995] Ac-T-hS-R-S-nL-(therapeutic agent) (SEQ ID NO: 423);

[0996] Ac-T-(1-Me)H-R-S-nL-(therapeutic agent) (SEQ ID NO: 424);

[0997] Ac-T-(3-Me)H-R-S-nL-(therapeutic agent) (SEQ ID NO: 425);

[0998] Ac-T-H-R-S-nL-(therapeutic agent) (SEQ ID NO: 426);

[0999] Ac-T-Sar-R-S-nL-(therapeutic agent) (SEQ ID NO: 427);

[1000] Ac-T-nV-R-S-nL-(therapeutic agent) (SEQ ID NO: 428);

[1001] Ac-T-nL-R-S-nL-(therapeutic agent) (SEQ ID NO: 429);

[1002] Ac-T-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 430);

[1003] Ac-T-Abu-R-S-nL-(therapeutic agent) (SEQ ID NO: 431);

[1004] Ac-4,4diMeThr-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 432);

[1005] Ac-hS-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 433);

[1006] Ac-hS-G-R-hS-Cha-(therapeutic agent) (SEQ ID NO: 434);

[1007] Ac-hS-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 435);

[1008] Ac-hS-G-R-T-Cha-(therapeutic agent) (SEQ ID NO: 436);

[1009] Ac-hS-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 437);

[1010] Ac-N-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 438);

[1011] Ac-Y-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 439);

[1012] Ac-Y-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 440);

[1013] Ac-Q-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 441);

[1014] Ac-Q-G-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 442);

[1015] Ac-L-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 573);

[1016] Ac-L-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 342);

[1017] Ac-L-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 343);

[1018] Ac-L-R-G-S-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 344);

[1019] Ac-L-R-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 345);

[1020] Ac-L-R-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO: 574);

[1021] Ac-L-R-G-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 346);

[1022] Ac-L-R-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 347);

[1023] Ac-L-R-G-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 348);

[1024] Ac-L-R-G-S-A-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 349);

[1025] Ac-L-R-G-S-A-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 350);

[1026] Ac-V-I-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 351);

[1027] Ac-V-I-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 352);

[1028] Ac-V-I-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 353);

[1029] Ac-V-I-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO: 354);

[1030] Ac-V-I-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO: 355);

[1031] Ac-V-I-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 356);

[1032] Ac-V-I-V-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 357);

[1033] Ac-V-I-V-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 358);

[1034] Ac-V-I-V-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 359);

[1035] Ac-R-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 360);

[1036] Ac-R-R-nV-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 361);

[1037] Ac-R-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO: 309);

[1038] Ac-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 310);

[1039] Ac-R-G-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 311);

[1040] Ac-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 312);

[1041] Ac-R-G-S-G-R--S-nL-(therapeutic agent) (SEQ ID NO: 313);

[1042] Ac-R-G-S-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 314);

[1043] Ac-R-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 315);

[1044] Ac-R-G-S-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 316);

[1045] Ac-R-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 317);

[1046] Ac-R-G-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 318);

[1047] Ac-R-G-S-A-R-S-S-(therapeutic agent) (SEQ ID NO: 319);

[1048] Ac-R-G-S-A-R-S-nV-(therapeutic agent) (SEQ ID NO: 320);

[1049] Ac-R-G-S-A-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 321);

[1050] Ac-R-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 322);

[1051] Ac-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 323);

[1052] Ac-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 324);

[1053] Ac-R-C(Me)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 325);

[1054] Ac-R-L-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 326);

[1055] Ac-R-V-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 327);

[1056] Ac-R-V-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 328);

[1057] Ac-R-nL-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 329);

[1058] Ac-R-G(tBu)-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 330);

[1059] Ac-R-L-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 331);

[1060] Ac-R-V-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 332);

[1061] Ac-R-nL-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 333);

[1062] Ac-I-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 334);

[1063] Ac-I-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 335);

[1064] Ac-I-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 336);

[1065] Ac-I-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO: 337);

[1066] Ac-I-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO: 338);

[1067] Ac-I-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 339);

[1068] Ac-I-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 340);

[1069] Ac-I-V-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 341);

[1070] Ac-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 585);

[1071] Ac-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 277);

[1072] Ac-G-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 278);

[1073] Ac-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 279);

[1074] Ac-G-S-G-R-L-(therapeutic agent) (SEQ ID NO: 280);

[1075] Ac-G-S-G-(4-guan)Phg-S-L-(therapeutic agent) (SEQ ID NO: 281);

[1076] Ac-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 282);

[1077] Ac-G-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 283);

[1078] Ac-G-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 284);

[1079] Ac-G-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 285);

[1080] Succ-bA-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 286);

[1081] Ac-G-T-G-R-S-hCha-(therapeutic agent) (SEQ ID NO: 287);

[1082] Ac-G-hS-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 288);

[1083] Ac-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO: 289);

[1084] Ac-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 290);

[1085] Ac-G-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 291);

[1086] Ac-G-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 292);

[1087] Ac-G-S-A-R-A-S-L-(therapeutic agent) (SEQ ID NO: 293);

[1088] Ac-V-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 294);

[1089] Ac-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 295);

[1090] Ac-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 296);

[1091] Ac-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 297);

[1092] Ac-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO: 298);

[1093] Ac-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO: 299);

[1094] Ac-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 300);

[1095] Ac-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 301);

[1096] Ac-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 302);

[1097] Ac-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 303);

[1098] Ac-C(Me)-P-G-R-A-L-(therapeutic agent) (SEQ ID NO: 304);

[1099] Ac-C(Me)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 305);

[1100] Ac-C(Me)-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 306);

[1101] Ac-C(Me)-P-A-R-A-S-L-(therapeutic agent) (SEQ ID NO: 307);and

[1102] Ac-G(tBu)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 308);

[1103] In another embodiment, the conjugates provided herein areselected from:

[1104] Ac-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 552);

[1105] Ac-Q-S-R-S-A-(therapeutic agent) (SEQ ID NO: 553);

[1106] Ac-Q-S-R-S-G-(therapeutic agent) (SEQ ID NO: 554);

[1107] Ac-R-S-R-A-A-(therapeutic agent) (SEQ ID NO: 555);

[1108] Ac-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 556);

[1109] Ac-R-Q-S-R-S-A-(therapeutic agent) (SEQ ID NO: 557); and

[1110] Ac-R-Q-S-R-S-A-A-(therapeutic agent) (SEQ ID NO: 558);

[1111] In another embodiment, the conjugates provided herein areselected from:

[1112] Ac-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 559);

[1113] Ac-S-G-R-A-A-(therapeutic agent) (SEQ ID NO: 560);

[1114] Ac-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 561);

[1115] Ac-S-G-R-S-S-A-(therapeutic agent) (SEQ ID NO: 562);

[1116] Ac-S-G-R-A-S-A-(therapeutic agent) (SEQ ID NO: 563);

[1117] Ac-S-G-R-S-G-(therapeutic agent) (SEQ ID NO: 564);

[1118] Ac-S-G-R-S-S-G-(therapeutic agent) (SEQ ID NO: 565);

[1119] Ac-S-G-R-S-G-A-(therapeutic agent) (SEQ ID NO: 566);

[1120] Ac-S-G-R-S-G-G-(therapeutic agent) (SEQ ID NO: 567); and

[1121] Ac-G-T-G-R-S-G-G-(therapeutic agent) (SEQ ID NO: 568);

[1122] In another embodiment, the conjugates provided herein areselected from:

[1123] Ac-L-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 597);

[1124] MeSO2-dA(Chx)-Abu-R-S-L-(therapeutic agent) (SEQ ID NO: 598);

[1125] Ac-R-A-R-S-L-(therapeutic agent) (SEQ ID NO: 599);

[1126] Ac-dA(Chx)-Abu-R-S-L-(therapeutic agent) (SEQ ID NO: 600);

[1127] Ac-dA(Chx)-Abu-R-S-S-L-(therapeutic agent) (SEQ ID NO: 601);

[1128] Ac-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 602);

[1129] MeOCO-dhF-P(OH)-R-S-S-L-(therapeutic agent) (SEQ ID NO: 603);

[1130] MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO: 604);

[1131] Ac-dCha-P(OH)-R-S-S-L-(therapeutic agent) (SEQ ID NO: 605);

[1132] Ac-dCha-Abu-R-S-S-A-(therapeutic agent) (SEQ ID NO: 606);

[1133] MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO: 607);

[1134] MeOCO-Quat3-G-R-S-L-(therapeutic agent) (SEQ ID NO: 608); and

[1135] MeOCO-Quat-G-R-S-L-(therapeutic agent) (SEQ ID NO: 609).

[1136] It also understood that conjugates containing the above peptidicsubstrate portions can be prepared with other capping groups in place ofAc (see, e.g., the description herein of the capping groups X^(n)).Therapeutic agents for use in the above conjugates include, for example,cytotoxic agents, such as, but not limited to, a toxin such as abrin,ricin A, pseudomonas exotoxin shiga toxin, diphtheria toxin and othersuch toxins and toxic portions thereof; proteins such as tumor necrosisfactor, interferons, such as α-interferon and gamma-interferon,pro-coagulants such as tissue factor and tissue factor variants,pro-apoptotic agents such FAS-ligand, nerve growth factor, plateletderived growth factor, tissue plasminogen activator; biological responsemodifiers such as, for example, lymphokines, interleukin-I (IL-I),interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophagecolony stimulating factor (GMCSF), granulocyte colony stimulating factor(G-CSF), fibroblast growth factors (FGFs) and other growth factors, themethotrexate group of drugs, the anthracycline family of drugs, thevinca alkaloid drugs, the mitomycins, the bleomycins, the cytotoxicnucleosides including cytosine arabinosides and difluoronucleosides, thepteridine family of drugs, diynenes, the taxanes and thepodophyllotoxins. All such conjugates are within the scope of theinstant disclosure and can be prepared and used as disclosed herein.

[1137] Thus, the conjugates provided herein include, but are not limitedto, those disclosed herein where the therapeutic agent is, e.g.,doxorubicin, carminomycin, daunorubicin, detorubicin, idarubicin,epirubicin, esorubicin, THP, AD-32, aminopterin, methotrexate,methopterin, dichloromethotrexate, mitomycin C, porfiromycin,5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, podophyllotoxin,or podophyllotoxin derivatives such as etoposide or etoposide phosphate,melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine,taxol, estramustine, cisplatin, combretastatin and analogs, andcyclophosphamide. In one embodiment, the therapeutic agent isdoxorubicin. In another embodiment, the therapeutic agent is taxol.

[1138] Any conjugates corresponding to the above conjugates or anyconjugates disclosed herein where the P1′ and/or P2′ residues are Ile inplace of Ala are within the scope of the instant disclosure and can beprepared and used as disclosed herein.

[1139] Any peptidic substrates formed by permutation and selection ofamino acids from those set forth in the above definitions of P groupsare contemplated.

D. Preparation of the Conjugates

[1140] The peptidic substrates of the conjugates provided herein aresynthesized from their constituent amino acids by conventional peptidesynthesis techniques, such as by solid-phase technology. The peptidicsubstrates are then purified by reverse-phase high performance liquidchromatography (HPLC).

[1141] The peptide acids can be prepared from their constituentFmoc-aminoacids. Standard methods of peptide synthesis are disclosed,for example, in the following works: Synthesis Notes Section,NovaBiochem Catalog 2002/3, Schroeder et al., “The Peptides”, Vol. 1,Academic Press 1965; Bodansky et al., “Peptide Synthesis”, IntersciencePublishers, 1966; McOmie (ed.) “Protective Groups in Organic Chemistry”,Plenum Press, 1973, Barany et al., “The Peptides: Analysis, Synthesis,Biology” 2, Chapter 1, Academic Press, 1990, and Stewart et al., “SolidPhase Peptide Synthesis”, Second Edition, Pierce Chemical Company, 1994.The disclosures of these references are hereby incorporated byreference.

[1142] The pharmaceutically acceptable salts of the conjugates providedherein include the conventional non-toxic salts of the conjugates asformed, e.g., from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like: and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic and the like.

[1143] The conjugates provided herein that contain the peptidic moietiescontaining the cell surface protease cleavage site and a therapeuticagent can similarly be synthesized by techniques known to those of skillin the art. For example, a free amine moiety on the therapeutic agentcan be covalently attached to the peptidic substrate at the carboxylterminus such that an amide bond is formed. Similarly, an amide bond canbe formed by covalently coupling an amine moiety of the peptidicsubstrate and a carboxyl moiety of the therapeutic agent. For thesepurposes a reagent such as2-(1H-benzotriazol-1-yl)-1,3,3-tetramethyl-uronium hexafluorophosphate(known as HBTU) and 1-hyroxybenzotriazole hydrate (known as HOBT),dicyclohexyl-carbodiimide (DCC),N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide (EDC),diphenyl-phosphorylazide (DPPA),benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP) and the like, used in combination orsingularly, can be utilized.

[1144] Furthermore, the instant conjugates can be formed by anon-peptidyl bond between the cell surface protease cleavage site and atherapeutic agent. For example, the therapeutic agent can be covalentlyattached to the carboxyl terminus of the peptidic substrate via ahydroxyl moiety on the therapeutic agent, thereby forming an esterlinkage. For this purpose a reagent such as a combination of HBTU andHOBT, a combination of BOP and imidazole, a combination of DCC and DMAP,and the like can be utilized. The carboxylic acid also can be activatedby forming the nitro-phenyl ester or the like and reacted in thepresence of DBU (1,8-diazabicyclo[5,4,O]undec-7-ene).

[1145] The instant conjugates also can be formed by attachment of thepeptidic substrate to the therapeutic agent via a linker unit. Suchlinker units include, for example, a biscarbonyl alkyl diradical wherebyan amine moiety on the therapeutic agent is connected with the linkerunit to form an amide bond and the amino terminus of the peptidicsubstrate is connected with the other end of the linker unit alsoforming an amide bond. Conversely, a diaminoalkyl diradical linker unit,whereby a carbonyl moiety on the cytotoxic agent is covalently attachedto one of the amines of the linker unit while the other amine of thelinker unit is covalently attached to the C-terminus of the peptidicsubstrate, also can be useful. Other such linker units which are stableto the physiological environment when not in the presence of a cellsurface protease, or a soluble, shed or released form thereof, but arecleavable upon the cleavage of the cell surface protease proteolyticcleavage site, or a soluble, shed or released form thereof, are alsoenvisioned. Furthermore, linker units can be utilized that, uponcleavage of the cell surface protease proteolytic cleavage site, remainattached to the therapeutic agent but do not significantly decrease thetherapeutic activity of such a post-cleavage therapeutic agentderivative when compared with an unmodified therapeutic agent.

[1146] One skilled in the art understands that in the synthesis of theconjugates provided herein, one can need to protect various reactivefunctionalities on the starting compounds and intermediates while adesired reaction is carried out on other portions of the molecule. Afterthe desired reactions are complete, or at any desired time, normallysuch protecting groups will be removed by, for example, hydrolytic orhydrogenolytic means. Such protection and deprotection steps areconventional in organic chemistry. One skilled in the art is referred toProtective Groups in Organic Chemistry, McOmie, ed., Plenum Press, NY,N.Y. (1973); and, Protective Groups in Organic Synthesis, Greene, ed.,John Wiley & Sons, NY, N.Y. (1991) for the teaching of protective groupswhich can be useful in the preparation of the conjugates providedherein.

[1147] By way of example only, useful amino-protecting groups caninclude, for example, C₁-C₁₀ alkanoyl groups such as formyl, acetyl,dichloroacetyl, propionyl, hexanoyl, 3,3-diethylhexanoyl,γ-chlorobutryl, and the like; C₁-C₁₀ alkoxycarbonyl and C₅-C₁₅aryloxycarbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl,allyloxycarbonyl, 4-nitrobenzyloxycarbonyl, fluorenylmethyloxycarbonyland cinnamoyloxy-carbonyl; halo(C₁-C₁₀)-alkoxycarbonyl such as2,2,2-trichloroethoxy-carbonyl; and C₁-C₁₅ arylalkyl and alkenyl groupsuch as benzyl, phenethyl, allyl, trityl, and the like. Other commonlyused amino-protecting groups are those in the form of enamines preparedwith β-keto-esters such as methyl or ethyl acetoacetate.

[1148] Useful carboxy-protecting groups can include, for example, C₁-C₁₀alkyl groups such as methyl, tert-butyl, decyl; halo C₁-C₁₀ alkyl suchas 2,2,2-trichloroethyl, and 2-iodoethyl; C₅-C₁₅ arylalkyl such asbenzyl, 4-methoxybenzy], 4-nitrobenzyl, triphenylmethyl,diphenyl-methyl; C₁-C₁₀ alkanoyloxymethyl such as acetoxy-methyl,propionoxymethyl and the like; and groups such as phenacyl,4-halophenacyl, allyl, dimethylallyl, tri-(C₁-C₃ alkyl)silyl, such astrimethylsilyl, β-p-toluenesulfonylethyl, β-p-nitrophenyl-thioethyl,2,4,6-trimethylbenzyl, β-methylthioethyl, phthalimidomethyl,2,4-dinitro-phenylsulphenyl, 2-nitrobenzhydryl and related groups.

[1149] Similarly, useful hydroxy protecting groups can include, forexample, the formyl group, the chloroacetyl group, the benzyl group, thebenzhydryl group, the trityl group, the 4-nitrobenzyl group, thetrimethylsilyl group, the phenacyl group, the tert-butyl group, themethoxymethyl group, the tetrahydropyranyl group, thetert-butyl-dimethylsilyl group and the like.

[1150] With respect to the embodiment of a peptidic substrate combinedwith the anthracycline antibiotic doxorubicin, the following ReactionSchemes illustrate the synthesis of the conjugates provided herein.

[1151] Reaction Scheme VI illustrates preparation of the conjugatesprovided herein of a peptidic substrate and the vinca alkaloid cytotoxicagent vinblastine wherein the attachment of vinblastine is at theC-terminus of the peptidic substrate. The use of the 1,3-diaminopropanelinker is illustrative only; other linker units between the carbonyl ofvinblastine and the C-terminus of the peptidic substrate are alsoenvisioned (e.g., (CH₂)_(u)—T—(CH₂)_(u)). The acyl azide startingmaterial is prepared from vinglasine by reaction with hydrazine (60-65°C., MeOH), followed by reaction with HCl/DMF/isoamyl nitrite.Furthermore, Reaction Scheme VI illustrates a synthesis of conjugateswherein the C4-hydroxy moiety is reacetylated following the addition ofthe linker unit. It is known that the desacetyl vinblastine conjugatealso is efficacious and can be prepared by eliminating the steps shownin Reaction Scheme VI of protecting the primary amine of the linker andreacting the intermediate with acetic anhydride, followed bydeprotection of the amine (see, e.g., International Patent ApplicationPublication No. WO 98/10651). Conjugation of the peptidic substrate atother positions and functional groups of vinblastine can be readilyaccomplished by one of ordinary skill in the art and also is expected toprovide conjugates that are substrates for cell surface proteases, or asoluble, shed or released form thereof.

[1152] Reaction Scheme VII illustrates preparation of certain of theconjugates utilized in the compositions and methods provided hereinwherein the peptidic substrates are combined with the vinca alkaloidcytotoxic agent vinblastine. Attachment of the N-terminus of thepeptidic substrate to vinblastine is illustrated (S. P. Kandukuri et al.(1985) J. Med. Chem. 28:1079-1088).

[1153] It also is understood that conjugates can be prepared wherein theN-terminus of the peptidic substrate utilized in the compositions andmethods provided herein is combined with one therapeutic agent, such asa cytotoxic agent, such as vinblastine, while the C-terminus issimultaneously attached to another cytotoxic agent, which is the same ordifferent cytotoxic agent, such as doxorubicin. Reaction Scheme VIIIillustrates the synthesis of such a polycytotoxic agent conjugate. Sucha polycytotoxic conjugate can offer advantages over a conjugatecontaining only one cytotoxic agent.

[1154] With respect to the embodiment of a peptidic substrate combinedwith desacetylvinblastine, the following Reaction Schemes IX and Xillustrate the synthesis of the conjugates provided herein.

[1155] Reaction Scheme IX illustrates preparation of conjugates providedherein containing the peptidic substrates provided herein and the vincaalkaloid cytotoxic agent vinblastine wherein the attachment of theoxygen of the 4-desacetylvinblastine is at the C-terminus of thepeptidic substrate. While other sequences of reactions can be useful informing such conjugates, it is known that initial attachment of a singleamino acid to the 4-oxygen and subsequent attachment of the remainingpeptidic substrate sequence to that amino acid is an exemplarary method(see, International Patent Application Publication No. WO 99/28345). Italso is known that 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine(ODHBT) can be utilized in place of HOAt in the final coupling step.

[1156] Reaction Scheme X illustrates preparation of conjugates of thepeptidic substrates provided herein wherein a hydroxy alkanoyl acid isused as a linker between the vinca drug and the peptidic substrate.

[1157] Taxol conjugates provided herein may be prepared by the generalmethod provided below. The preparation of 7-Ala-Taxol and 7-Gly-Taxol isdisclosed in Mathew et al (1992) J. Med. Chem. 35:145-151.

E. Formulation and Administration of Pharmaceutical Compositions

[1158] The conjugates and compositions provided herein are used fortreating, preventing, or ameliorating one or more symptoms of anydisease or disorder that can be treated by targeting a cell or tissuethat expresses a cell surface protease, particularly, a serine protease,on its surface at higher levels compared to other cells, or soluble,shed or released forms thereof. These include, but are not limited to,hyperproliferative diseases, such as cancer, any disease associated withaberrant or excessive angiogenesis, autoimmune disorders, inflammatorydiseases and any other disease for which an appropriate cell surfaceprotease, including cell-associated and cell-localized proteases, can beidentified.

[1159] The pharmaceutical compositions provided herein containtherapeutically effective amounts of one or more of the conjugatesprovided herein that are useful in the prevention, treatment, oramelioration of one or more of the symptoms of diseases or disordersassociated with undesired and/or uncontrolled angiogenesis orneovascularization. Such diseases or disorders include, but are notlimited to, solid neoplasms, including lung, colon, esophageal, breast,ovarian and prostate cancers; vascular malformations and cardiovasculardisorders, including, but not limited to, angiofibroma, angiolipoma,atherosclerosis, restenosis/reperfusion injury, arteriovenousmalformations, hemangiomatosis and vascular adhesions, dyschondroplasiawith vascular hematomas, hereditary hemorrhagic telangiectasia and VonHipple Lindau syndrome; chronic inflammatory diseases and abherent woundrepairs, including, but not limited to, diabetes mellitus, hemophiliacjoints, inflammatory bowel disease, nonhealing fractures, rapidlyprogressing periodontitis, juvenile periodontitis, psoriasis, rheumatoidarthritis, venous stasis ulcers, granulations-burns, hypertrophic scars,liver cirrhosis, osteoradionecrosis, postoperative adhesions, pyogenicgranuloma and systemic sclerosis; circulatory disorders, including, butnot limited to, Raynaud's phenomenon; crest syndromes, including, butnot limited to, calcinosis, esophageal, dyomotiloty, sclerodactyly andteangiectasis; dermatological disorders, including, but not limited to,systemic vasculitis, scleroderma, pyoderma gangrenosum, vasculopathy,venous, arterial ulcers, Sturge-Weber syndrome, Port-wine stains, bluerubber bleb nevus syndrome, Klippel-Trenaunay-Weber syndrome andOsler-Weber-Rendu syndrome; and ocular disorders, including, but notlimited to, blindness caused by ocular neovascular disease, cornealgraft neovascularization, macular degeneration in the eye, neovascularglaucoma, trachoma, diabetic retinopathy, myopic degeneration,retinopathy of prematurity, retrolental fibroplasia and cornealneovascularization.

[1160] The compositions contain one or more conjugates provided herein.The conjugates can be formulated into suitable pharmaceuticalpreparations such as, for example, solutions, suspensions, tablets,dispersible tablets, pills, capsules, powders, sustained releaseformulations or elixirs, for oral administration or in sterile solutionsor suspensions for parenteral administration, as well as transdermalpatch preparation and dry powder inhalers. Typically the cojugatesdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art (see, e.g., Ansel (1985)Introduction to Pharmaceutical Dosage Forms, Fourth Edition, p. 126)).Effective concentrations can be empirically determined using animalmodels, in vitro models or test subjects.

[1161] In the compositions, effective concentrations of one or moreconjugates or pharmaceutically acceptable derivatives thereof is (are)mixed with a suitable pharmaceutical carrier or vehicle. The conjugatescan be derivatized as the corresponding salts, esters, enol ethers oresters, acids, bases, solvates or hydrates prior to formulation, asdescribed above. The concentrations of the conjugates in thecompositions are effective for delivery of an amount, uponadministration, that treats, prevents, or ameliorates one or more of thesymptoms of diseases or disorders associated with undesired and/oruncontrolled angiogenesis or neovascularization. Such diseases ordisorders include, but are not limited to, solid neoplasms; vascularmalformations and cardiovascular disorders, including, but not limitedto, angiofibroma, angiolipoma, atherosclerosis, restenosis/reperfusioninjury, arteriovenous malformations, hemangiomatosis and vascularadhesions, dyschondroplasia with vascular hamartomas, hereditaryhemorrhagic telangiectasia and Von Hipple Lindau syndrome; chronicinflammatory diseases and abherent wound repairs, including, but notlimited to, diabetes mellitus, hemophiliac joints, inflammatory boweldisease, nonhealing fractures, rapidly progressing periodontitis,juvenile periodontitis, psoriasis, rheumatoid arthritis, venous stasisulcers, granulations-burns, hypertrophic scars, liver cirrhosis,osteoradionecrosis, postoperative adhesions, pyogenic granuloma andsystemic sclerosis; circulatory disorders, including, but not limitedto, Raynaud's phenomenon; crest syndromes, including, but not limitedto, calcinosis, esophageal, dyomotiloty, sclerodactyly andteangiectasis; dermatological disorders, including, but not limited to,systemic vasculitis, scleroderma, pyoderma gangrenosum, vasculopathy,venous, arterial ulcers, Sturge-Weber syndrome, Port-wine stains, bluerubber bleb nevus syndrome, Klippel-Trenaunay-Weber syndrome andOsler-Weber-Rendu syndrome; and ocular disorders, including, but notlimited to, blindness caused by ocular neovascular disease, cornealgraft neovascularization, macular degeneration in the eye, neovascularglaucoma, trachoma, diabetic retinopathy, myopic degeneration,retinopathy of prematurity, retrolental fibroplasia and cornealneovascularization.

[1162] The conjugates herein can be formulated into pharmaceuticalcompositions suitable for topical, local, intravenous and systemicapplication. Effective concentrations of one or more of the conjugatesare mixed with a suitable pharmaceutical carrier or vehicle. Theconcentrations or amounts of the conjugates that are effective requiresdelivery of an amount, upon administration, that ameliorates thesymptoms or treats the disease. Typically, the compositions areformulated for single dosage administration. Therapeutically effectiveconcentrations and amounts can be determined empirically by testing theconjugates in known in vitro and in vivo systems, such as thosedescribed here; dosages for humans or other animals can then beextrapolated therefrom.

[1163] Upon mixing or addition of the conjugate(s) with the vehicle, theresulting mixture can be a solution, suspension, emulsion or other suchcomposition. The form of the resulting mixture depends upon a number offactors, including the intended mode of administration and thesolubility of the conjugate in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe disease, disorder or condition treated and can be empiricallydetermined based upon in vitro and/or in vivo data, such as the datafrom the mouse xenograft model for tumors or rabbit ophthalmic model. Ifnecessary, pharmaceutically acceptable salts or other derivatives of theconjugates can be prepared.

[1164] Pharmaceutical carriers or vehicles suitable for administrationof the conjugates provided herein include any such carriers known tothose skilled in the art to be suitable for the particular mode ofadministration. In addition, the conjugates can be formulated as thesole pharmaceutically active ingredient in the composition or can becombined with other active ingredients.

[1165] The conjugates can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid, semi-liquid or solid form andare formulated in a manner suitable for each route of administration.Exemplary modes of administration depend upon the indication treated.Dermatological and ophthalmologic indications will typically be treatedlocally; whereas, tumors and vascular proliferative disorders, willtypically be treated by systemic, intradermal or intramuscular, modes ofadministration.

[1166] The conjugate is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. It isunderstood that number and degree of side effects depends upon thecondition for which the conjugates are administered. For example,certain toxic and undesirable side effects are tolerated when treatinglife-threatening illnesses, such as tumors, that would not be toleratedwhen treating disorders of lesser consequence.

[1167] The concentration of conjugate in the composition will depend onabsorption, inactivation and excretion rates thereof, the dosageschedule, and amount administered as well as other factors known tothose of skill in the art.

[1168] Typically a therapeutically effective dosage should produce aserum concentration of active ingredient of from about 0.1 ng/ml toabout 50-100 μg/ml. The pharmaceutical compositions typically shouldprovide a dosage of from about 0.01 mg to about 100-2000 mg ofconjugate, depending upon the conjugate selected as adjusted for bodysurface area and/or weight. Typically, for intravenous or systemictreatment a daily dosage of about between 0.05 and 0.5 mg/kg should besufficient. Local application for ophthalmic disorders should provideabout 1 ng up to 100 μg, generally about 1 μg to about 10 μg, per singledosage administration. It is understood that the amount to administer isa function of the conjugate selected, the indication treated, andpossibly the side effects that will be tolerated. Dosages can beempirically determined using recognized models for each disorder.

[1169] Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofconjugate is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the conjugates provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

[1170] In addition, the conjugates can be formulated as the soleingredient in the composition or can be combined with other activeingredients. Liposomal suspensions, including tissue-targeted liposomes,particularly tumor-targeted liposomes, also can be suitable aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art. For example, liposomeformulations can be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) can be formedby drying down egg phosphatidyl choline and brain phosphatidyl serine(7:3 molar ratio) on the inside of a flask. A solution of a conjugateprovided herein in phosphate buffered saline lacking divalent cations(PBS) is added and the flask shaken until the lipid film is dispersed.The resulting vesicles are washed to remove unencapsulated conjugate,pelleted by centrifugation, and then resuspended in PBS.

[1171] The conjugate is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration can be determined empirically bytesting the conjugates in in vitro and in vivo systems described herein(see, e.g., EXAMPLES 3 and 4) and then extrapolated therefrom fordosages for humans.

[1172] The concentration of conjugate in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theconjugate, the physicochemical characteristics of the conjugate, thedosage schedule, and amount administered as well as other factors knownto those of skill in the art. For example, the amount that is deliveredis sufficient to ameliorate one or more of the symptoms of diseases ordisorders associated with undesired and/or uncontrolled angiogenesis orneovascularization, as described herein.

[1173] Typically a therapeutically effective dosage should produce aserum concentration of active ingredient of from about 0.1 ng/ml toabout 50-100 μg/ml. The pharmaceutical compositions typically shouldprovide a dosage of from about 0.001 mg to about 2000 mg of conjugateper kilo-gram of body weight per day. Pharmaceutical dosage unit formsare prepared to provide from about 1 mg to about 1000 mg and generallyfrom about 10 to about 500 mg of the essential active ingredient or acombination of essential ingredients per dosage unit form.

[1174] The conjugate can be administered at once, or can be divided intoa number of smaller doses to be administered at intervals of time. It isunderstood that the precise dosage and duration of treatment is afunction of the disease being treated and can be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuescan also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

[1175] Exemplary pharmaceutically acceptable derivatives include acids,bases, enol ethers and esters, salts, esters, hydrates, solvates andconjugate forms. The derivative is selected such that itspharmacokinetic properties are superior to the corresponding neutralconjugate.

[1176] Thus, effective concentrations or amounts of one or more of theconjugates described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Conjugates are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingdiseases or disorders associated with undesired and/or uncontrolledangiogenesis or neovascularization, as described herein. Theconcentration of conjugate in the composition will depend on absorption,inactivation, excretion rates of the conjugate, the dosage schedule,amount administered, particular formulation as well as other factorsknown to those of skill in the art.

[1177] The compositions are intended to be administered by a suitableroute, including orally, parenterally, rectally, topically and locally.For oral administration, capsules and tablets are generally employed.The compositions are in liquid, semi-liquid or solid form and areformulated in a manner suitable for each route of administration.Exemplary modes of administration include parenteral and oral modes ofadministration.

[1178] Solutions or suspensions used for parenteral, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent, such as water for injection, salinesolution, fixed oil, polyethylene glycol, glycerine, propylene glycol orother synthetic solvent; antimicrobial agents, such as benzyl alcoholand methyl parabens; antioxidants, such as ascorbic acid and sodiumbisulfite; chelating agents, such as ethylenediaminetetraacetic acid(EDTA); buffers, such as acetates, citrates and phosphates; and agentsfor the adjustment of tonicity such as sodium chloride or dextrose.Parenteral preparations can be enclosed in ampules, disposable syringesor single or multiple dose vials made of glass, plastic or othersuitable material.

[1179] In instances in which the conjugates exhibit insufficientsolubility, methods for solubilizing conjugates can be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN®, or dissolution in aqueous sodiumbicarbonate. Derivatives of the conjugates also can be used informulating effective pharmaceutical compositions.

[1180] Upon mixing or addition of the conjugate(s), the resultingmixture can be a solution, suspension, emulsion or the like. The form ofthe resulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the conjugate inthe selected carrier or vehicle. The effective concentration issufficient for ameliorating the symptoms of the disease, disorder orcondition treated and can be empirically determined.

[1181] The pharmaceutical compositions are provided for administrationto humans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the conjugates or pharmaceutically acceptablederivatives thereof. The conjugates and derivatives thereof aretypically formulated and administered in unit-dosage forms ormultiple-dosage forms. Unit-dose forms as used herein refers tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the conjugate sufficient to produce thedesired therapeutic effect, in association with the requiredpharmaceutical carrier, vehicle or diluent. Examples of unit-dose formsinclude ampoules and syringes and individually packaged tablets orcapsules. Unit-dose forms can be administered in fractions or multiplesthereof. A multiple-dose form is a plurality of identical unit-dosageforms packaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

[1182] The composition can contain along with the conjugate: a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethyl-cellulose; a lubricant, such as magnesium stearate,calcium stearate and talc; and a binder such as starch, natural gums,such as gum acacia-gelatin, glucose, molasses, polyvinylpyrrolidine,celluloses and derivatives thereof, povidone, crospovidones and othersuch binders known to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing a conjugate as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered can also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrine derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of theconjugate in an amount sufficient to alleviate the symptoms of thetreated subject.

[1183] Dosage forms or compositions containing active ingredient in therange of 0.005% to 100% with the balance made up from non-toxic carriercan be prepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions can contain 0.001%-100% activeingredient, such as 0.1-85%, for example 75-95%.

[1184] The conjugates or pharmaceutically acceptable derivatives can beprepared with carriers that protect the conjugate against rapidelimination from the body, such as time release formulations orcoatings. The compositions can include other conjugates to obtaindesired combinations of properties. The conjugates provided herein, orpharmaceutically acceptable derivatives thereof as described herein,also can be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as diseases ordisorders associated with undesired and/or uncontrolled angiogenesis orneovascularization. It is to be understood that such combination therapyconstitutes a further aspect of the compositions and methods oftreatment provided herein.

[1185] 1. Compositions for Oral Administration

[1186] Oral pharmaceutical dosage forms are either solid, gel or liquid.The solid dosage forms are tablets, capsules, granules, and bulkpowders. Types of oral tablets include compressed, chewable lozenges andtablets which can be enteric-coated, sugar-coated or film-coated.Capsules can be hard or soft gelatin capsules, while granules andpowders can be provided in non-effervescent or effervescent form withthe combination of other ingredients known to those skilled in the art.

[1187] In certain embodiments, the formulations are solid dosage forms,such as, for example, capsules or tablets. The tablets, pills, capsules,troches and other dosage forms can contain, for example, any of thefollowing ingredients, or compounds of a similar nature: a binder; adiluent; a disintegrating agent; a lubricant; a glidant; a sweeteningagent; and a flavoring agent.

[1188] Examples of binders include microcrystalline cellulose, gumtragacanth, glucose solution, acacia mucilage, gelatin solution, sucroseand starch paste. Lubricants include talc, starch, magnesium or calciumstearate, lycopodium and stearic acid. Diluents include, for example,lactose, sucrose, starch, kaolin, salt, mannitol and dicalciumphosphate. Glidants include, but are not limited to, colloidal silicondioxide. Disintegrating agents include crosscarmellose sodium, sodiumstarch glycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of conjugates whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

[1189] If oral administration is desired, the conjugate could beprovided in a composition that protects it from the acidic environmentof the stomach. For example, the composition can be formulated in anenteric coating that maintains its integrity in the stomach and releasesthe conjugate in the intestine. The composition also can be formulatedin combination with an antacid or other such ingredient.

[1190] When the dosage unit form is a capsule, it can contain, inaddition to material of the above type, a liquid carrier such as a fattyoil. In addition, dosage unit forms can contain various other materialswhich modify the physical form of the dosage unit, for example, coatingsof sugar and other enteric agents. The conjugates also can beadministered as a component of an elixir, suspension, syrup, wafer,sprinkle, chewing gum or the like. A syrup can contain, in addition tothe conjugates, sucrose as a sweetening agent and certain preservatives,dyes and colorings and flavors.

[1191] The conjugates also can be mixed with other active materialswhich do not impair the desired action, or with materials thatsupplement the desired action, such as antacids, H2 blockers, anddiuretics. Higher concentrations, up to about 98% by weight of theconjugate can be included.

[1192] Pharmaceutically acceptable carriers included in tablets arebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, and wetting agents. Enteric-coated tablets, because ofthe enteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents also can be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

[1193] Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[1194] Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and can contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

[1195] Solvents include glycerin, sorbitol, ethyl alcohol and syrup.Examples of preservatives include glycerin, methyl and propylparaben,benzoic add, sodium benzoate and alcohol. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Examples of emulsifying agents include gelatin, acacia, tragacanth,bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.Suspending agents include sodium carboxymethylcellulose, pectin,tragacanth, Veegum and acacia. Diluents include lactose and sucrose.Sweetening agents include sucrose, syrups, glycerin and artificialsweetening agents such as saccharin. Wetting agents include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether. Organic adds include citric andtartaric acid. Sources of carbon dioxide include sodium bicarbonate andsodium carbonate. Coloring agents include any of the approved certifiedwater soluble FD and C dyes, and mixtures thereof. Flavoring agentsinclude natural flavors extracted from plants such fruits, and syntheticblends of conjugates which produce a pleasant taste sensation.

[1196] For a solid dosage form, the solution or suspension, in forexample propylene carbonate, vegetable oils or triglycerides, forexample the formulation can be encapsulated in a gelatin capsule. Suchsolutions, and the preparation and encapsulation thereof, are disclosedin U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquiddosage form, the solution, e.g., for example, in a polyethylene glycol,can be diluted with a sufficient quantity of a pharmaceuticallyacceptable liquid carrier, e.g., water, to be easily measured foradministration.

[1197] Alternatively, liquid or semi-solid oral formulations can beprepared by dissolving or dispersing the conjugate or derivative thereofin vegetable oils, glycols, triglycerides, propylene glycol esters(e.g., propylene carbonate) and other such carriers, and encapsulatingthese solutions or suspensions in hard or soft gelatin capsule shells.Other useful formulations include those set forth in U.S. Pat. Nos. Re28,819 and 4,358,603. Briefly, such formulations include, but are notlimited to, those containing a conjugate provided herein, a dialkylatedmono- or poly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more anitoxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

[1198] Other formulations include, but are not limited to, aqueousalcoholic solutions including a pharmaceutically acceptable acetal.Alcohols used in these formulations are any pharmaceutically acceptablewater-miscible solvents having one or more hydroxyl groups, including,but not limited to, propylene glycol and ethanol. Acetals include, butare not limited to, di(lower alkyl) acetals of lower alkyl aldehydessuch as acetaldehyde diethyl acetal.

[1199] In all embodiments, tablets and capsules formulations can becoated as known by those of skill in the art in order to modify orsustain dissolution of the conjugate. Thus, for example, they can becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

[1200] 2. Injectables, Solutions and Emulsions

[1201] Parenteral administration, generally characterized by injection,either subcutaneously, intramuscularly or intravenously also iscontemplated herein. Injectables can be prepared in conventional forms,either as liquid solutions or suspensions, solid forms suitable forsolution or suspension in liquid prior to injection, or as emulsions.Suitable excipients are, for example, water, saline, dextrose, glycerolor ethanol. In addition, if desired, the pharmaceutical compositions tobe administered can also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow-release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) also is contemplated herein. Briefly, aconjugate provided herein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The conjugate diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of conjugate contained in suchparenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the conjugate and the needs of thesubject.

[1202] Parenteral administration of the compositions includesintravenous, subcutaneous and intramuscular administrations.Preparations for parenteral administration include sterile solutionsready for injection, sterile dry soluble products, such as lyophilizedpowders, ready to be combined with a solvent just prior to use,including hypodermic tablets, sterile suspensions ready for injection,sterile dry insoluble products ready to be combined with a vehicle justprior to use and sterile emulsions. The solutions can be either aqueousor nonaqueous.

[1203] If administered intravenously, suitable carriers includephysiological saline or phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents, such as glucose,polyethylene glycol, and polypropylene glycol and mixtures thereof.

[1204] Pharmaceutically acceptable carriers used in parenteralpreparations include aqueous vehicles, nonaqueous vehicles,antimicrobial agents, isotonic agents, buffers, antioxidants, localanesthetics, suspending and dispersing agents, emulsifying agents,sequestering or chelating agents and other pharmaceutically acceptablesubstances.

[1205] Examples of aqueous vehicles include Sodium Chloride Injection,Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

[1206] The concentration of the conjugate is adjusted so that aninjection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

[1207] The unit-dose parenteral preparations are packaged in an ampule,a vial or a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

[1208] Illustratively, intravenous or intraarterial infusion of asterile aqueous solution containing a conjugate is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing a conjugate injected as necessary to producethe desired pharmacological effect.

[1209] Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,genrally more than 1% w/w of the conjugate to the treated tissue(s). Theconjugate can be administered at once, or can be divided into a numberof smaller doses to be administered at intervals of time. It isunderstood that the precise dosage and duration of treatment is afunction of the tissue being treated and can be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuescan also vary with the age of the individual treated. It is to befurther understood that for any particular subject, specific dosageregimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the formulations, and that the concentrationranges set forth herein are exemplary only and are not intended to limitthe scope or practice of the claimed formulations.

[1210] The conjugate can be suspended in micronized or other suitableform or can be derivatized to produce a more soluble product. The formof the resulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the conjugate inthe selected carrier or vehicle. The effective concentration issufficient for ameliorating the symptoms of the condition and can beempirically determined.

[1211] 3. Lyophilized Powders

[1212] Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They also can be reconstituted and formulated as solids orgels.

[1213] The sterile, lyophilized powder is prepared by dissolving aconjugate provided herein, or a pharmaceutically acceptable derivativethereof, in a suitable solvent. The solvent can contain an excipientwhich improves the stability or other pharmacological component of thepowder or reconstituted solution, prepared from the powder. Excipientsthat can be used include, but are not limited to, dextrose, sorbital,fructose, corn syrup, xylitol, glycerin, glucose, sucrose or othersuitable agent. The solvent can also contain a buffer, such as citrate,sodium or potassium phosphate or other such buffer known to those ofskill in the art at, typically, about neutral pH. Subsequent sterilefiltration of the solution followed by lyophilization under standardconditions known to those of skill in the art provides the desiredformulation. Generally, the resulting solution will be apportioned intovials for lyophilization. Each vial will contain a single dosage (suchas 10-1000 mg, for example 100-500 mg) or multiple dosages of theconjugate. The lyophilized powder can be stored under appropriateconditions, such as at about 4° C. to room temperature.

[1214] Reconstitution of this lyophilized powder with water forinjection provides a formulation for use in parenteral administration.For reconstitution, generally about 1-50 mg, such 5-35 mg or about 9-30mg of lyophilized powder, is added per mL of sterile water or othersuitable carrier. The precise amount depends upon the selectedconjugate, intended subject, and other empircally determinableparameters. Hence the amount can be empirically determined.

[1215] 4. Topical Administration

[1216] Topical mixtures are prepared as described for the local andsystemic administration. The resulting mixture can be a solution,suspension, emulsions or the like and are formulated as creams, gels,ointments, emulsions, solutions, elixirs, lotions, suspensions,tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories,bandages, dermal patches or any other formulations suitable for topicaladministration.

[1217] The conjugates or pharmaceutically acceptable derivatives thereofcan be formulated as aerosols for topical application, such as byinhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and4,364,923, which describe aerosols for delivery of a steroid useful fortreatment of inflammatory diseases, particularly asthma). Theseformulations for administration to the respiratory tract can be in theform of an aerosol or solution for a nebulizer, or as a microfine powderfor insufflation, alone or in combination with an inert carrier such aslactose. In such a case, the particles of the formulation will typicallyhave diameters of less than 50 microns, generally less than 10 microns.

[1218] The conjugates can be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye or for intracisternal or intraspinalapplication. Topical administration is contemplated for transdermaldelivery and also for administration to the eyes or mucosa, or forinhalation therapies. Nasal solutions of the conjugate alone or incombination with other pharmaceutically acceptable excipients also canbe administered.

[1219] These solutions, particularly those intended for ophthalmic use,can be formulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

[1220] 5. Compositions for other Routes of Administration

[1221] Other routes of administration, such as topical application,transdermal patches, and rectal administration are also contemplatedherein.

[1222] For example, pharmaceutical dosage forms for rectaladministration are rectal suppositories, capsules and tablets forsystemic effect. Rectal suppositories are used herein mean solid bodiesfor insertion into the rectum which melt or soften at body temperaturereleasing one or more conjugates. Pharmaceutically acceptable substancesutilized in rectal suppositories are bases or vehicles and agents toraise the melting point. Examples of bases include cocoa butter(theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) andappropriate mixtures of mono-, di- and triglycerides of fatty acids.Combinations of the various bases can be used. Agents to raise themelting point of suppositories include spermaceti and wax. Rectalsuppositories can be prepared either by the compressed method or bymolding. The typical weight of a rectal suppository is about 2 to 3 gm.

[1223] Tablets and capsules for rectal administration are manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

[1224] 6. Articles of Manufacture

[1225] The conjugates or pharmaceutically acceptable derivatives can bepackaged as articles of manufacture containing packaging material, aconjugate or pharmaceutically acceptable derivative thereof providedherein, which is used for treatment, prevention or amelioration of oneor more symptoms associated with proliferative diseases or disorders,and a label that indicates that the conjugate or pharmaceuticallyacceptable derivative thereof is used for treatment, prevention oramelioration of one or more symptoms associated with proliferativediseases or disorders.

[1226] The articles of manufacture provided herein contain packagingmaterials. Packaging materials for use in packaging pharmaceuticalproducts are well known to those of skill in the art. See, e.g., U.S.Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceuticalpackaging materials include, but are not limited to, blister packs,bottles, tubes, inhalers, pumps, bags, vials, containers, syringes,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment. A wide array offormulations of the conjugates and compositions provided herein arecontemplated as are a variety of treatments for any disorder in which acell surface protease, or a soluble, shed or secreted form thereof, isimplicated.

F. Evaluation of the Activity of the Conjugates

[1227] Standard physiological, pharmacological and biochemicalprocedures are available for testing the conjugates to identify thosethat possess therapeutic activity upon action of a cell surface proteaseor a soluble, shed, or released form thereof. In vitro and in vivoassays that can be used to evaluate therapeutic activity, such ascytotoxicity, of the conjugates will depend upon the therapeutic agentbeing tested.

[1228] Exemplary assays are discussed briefly below with reference tocytotoxic conjugates (see, also, Examples). It is understood that theparticular activity assayed will depend upon the conjugated therapeuticagent.

[1229] 1. In Vitro Assays

[1230] The therapeutic activity, such as cytotoxicity, of the conjugatesprovided herein can assessed by any assays normally used for assessingthe therapeutic activity, such as cytotoxicity, of the unconjugatedtherapeutic agent. Numerous such assays are known, for example, assayscan employ cells that express the targeted cell surface protease and thetherapeutic activity of the therapeutic agent is assessed. For example,cytoxicity can be assessed by measuring cell viability or by measuringcell proliferation, such as by incorporation of a labeled nucleotide orother such label. Generally the activity is compared with cells that donot express the targeted protease.

[1231] For example, the cells will be any that express a targeted MTSPor endotheliase. Such cells can be obtained by choosing cells known toexpress the cell surface protease, such as by determining tissueexpression profiles, as discussed above, or by screening a variety ofcell lines with an antibody for a targeted protease, or for the proteaseactivity in the presence of a labeled, such as a chromogenic, substratefor the protease in the presence and absence of a known inhibitor of thetargeted protease.

[1232] Alternatively, nucleic acid encoding the protease can beintroduced in a cell line that does not express the protease, andexpressed therein to produce a cell line that expresses the protease ofinterest. The resulting recombinant cells can be used in cytotoxicityassays.

[1233] 2. In Vivo Assays

[1234] Numerous animal models for assessing therapeutic activity areknown. Any suitable in vivo model can be used. Exemplary are the mousexenograft model and chicken embryo models.

[1235] Chicken Embryo Model

[1236] The CAM model (chick embryo chorioallantoic membrane model;Ossowski (1988) J. Cell Biol. 107:2437-2445), provides another methodfor evaluating the inhibitory activity of a test compound. In the CAMmodel, tumor cells invade through the chorioallantoic membranecontaining CAM (with tumor cells in the presence of several serineprotease inhibitors results in less or no invasion of the tumor cellsthrough the membrane). Thus, the CAM assay is performed with CAM andtumor cells in the presence and absence of various concentrations oftest compound. The invasiveness of tumor cells is measured under suchconditions to provide an indication of the compound's inhibitoryactivity. A compound having inhibitory activity correlates with lesstumor invasion.

[1237] Thus, the CAM assay is performed with CAM and tumor cells in thepresence and absence of various concentrations of a test compound. Acompound having activity correlates with a change in tumor invasionand/or tumor growth.

[1238] For example, the ability of a cell surface protease to liberate atherapeutic agent, such as a cytotoxic agent, or the activity of aconjugate agent can be assessed using this model. If the therapeuticagent is released from the compound and it is an inhibitory agent therewill be less tumor invasion or a decrease in size of the tumor. If thetherapeutic agent is inactive in the conjugate, there will be no effecton tumor invasion.

[1239] The CAM model also is used in a standard assay of angiogenesis(i.e., effect on formation of new blood vessels (Brooks et al. (1991)Methods in Molecular Biology 129:257-269). According to this model, afilter disc containing an angiogenesis inducer, such as basic fibroblastgrowth factor (bFGF) is placed onto the CAM. Diffusion of the cytokineinto the CAM induces local angiogenesis, which can be measured inseveral ways such as by counting the number of blood vessel branchpoints within the CAM directly below the filter disc. The ability ofidentified compounds to inhibit cytokine-induced angiogenesis can betested using this model. A test compound can either be added to thefilter disc that contains the angiogenesis inducer, be placed directlyon the membrane or be administered systemically. The extent of new bloodvessel formation in the presence and/or absence of test compound can becompared using this model. The formation of fewer new blood vessels inthe presence of a test compound would be indicative of anti-angiogenesisactivity.

[1240] This can be adapted for use with the conjugates herein to 1)assess the activity of a therapeutic agent in the conjugate; and 2) toassess the ability of a particular cell surface protease to liberate atherapeutic agent from a conjugate.

[1241] Mouse Xenograft Model

[1242] In vivo activity can be a assessed using recognized animalmodels, such as the well-known mouse xenograft model for anti-tumoractivity (see, e.g., Beitz et al. (1992) Cancer Research 52:227-230;Houghton et al. (1982) Cancer Res. 42:535-539; Bogden et al. (1981)Cancer (Philadelphia) 48:10-20; Hoogenhout et al. (1983) Int. J. Radiat.Oncol., Biol. Phys. 9:871-879; Stastny et al. (1993) Cancer Res.53:5740-5744). The in vivo mouse solid tumor xenograft model is used inassays for that test an agent's ability to inhibit tumor cellproliferation and/or spontaneous metastasis. For example, a conjugate isevaluated for anti-tumor activity against any tumor subtype thatexpresses the targeted cell surface protease, e.g., an ovarian tumor, ina mouse tumor xenograft model. Nude mice are given one or more, such asfour intravenous injections of the conjugate. Dosing material isprepared by mixing the test material with appropriate volumes of, forexample, PBS/0.1% BSA to achieve the desired doses. Mice IV injections(250-300 ul) into the tail vein for the duration of the experiment, suchas, for example, days 5, 12, 19 and 26, with day 1 designated as the daythat the tumor cells are injected into the mice. Doses are either fixedor normalized for differences in body weight. Tumor volume is measuredtwice weekly for a selected period.

[1243] Female Balb/c nu/nu athymic mice (Roger Williams Hospital AnimalFacility, Providence, R.I.), 8-12 weeks old are suitable mice. Theyshould be maintained in an aseptic environment and selected such thatbody weights range from about 25-30 grams the day prior to dosing.Animals are maintained in a quarantined room and handled under asepticconditions. Food and water are supplied ad libitum. Appropriate tumorcells can be obtained, for example, from the American Type CultureCollection (Rockville, Md.) and grown in modified Eagle's mediumsupplemented with 10% fetal calf serum. A selected number of days, suchas five days prior to injection of the test material, mice receive asubcutaneous injection of tumor cells in the right rear flank.

[1244] Calipers are used to measure the dimensions of each tumor.Measurements (mm) of maximum and minimum width are performed prior toinjection of the test material and at selected, such as bi-weekly,intervals for the duration of the experiment. Tumor volumes (mm³) can becomputed, for example, using the formula:

Volume=[(width)²(length)]/2.

G. Methods for Identifying Proteases to Target

[1245] Also provided are methods for identifying proteases to targetconjugates for treatment of diseases. The methods involve identifyingcell-surface protease-associated disease by identifying a cell involvedin the disease process or a cell in the vicinity of the cell involved inthe disease process. For example, if disease involves a particulartumor, a protease present on the particular tumor or on cells that alocated in the vicinity thereof is identified. A cell surface proteaseon the cell for targeting and substrates therefor are then identified.Conjugates that target such proteases as provided herein can then beprepared.

[1246] The following examples are included for illustrative purposesonly and are not intended to limit the scope of the invention.

EXAMPLE 1 General Procedures for Preparing Peptide-DoxorubicinConjugates

[1247] Step A: Synthesis of Peptides on Wang Resin

[1248] Peptides were prepared automatically using an ABI 431A peptidesynthesizer from Perseptive Biosystems on preloaded Wang resin (0.25mmol). The ABI 431A uses HOBT, HBTU, DIEA activation. The synthesis ofN-acetyl (or other amide) capped peptides involved the use of AcOH (orother respective carboxylic acid) during the final coupling step on theABI 431A. Other N-terminal caps where attached manually by using thefollowing reagents: For carbamates and sulfonamides the peptides werecapped with ROCOCl or RSO₂Cl and DIEA (4 equivalents each, 1 hr) in DMF(3 mL).

[1249] Step B: Cleavage of Peptides from Wang Resin

[1250] The cleavage of peptides from Wang resin involved shaking theresin with 2 mL TFA/H₂O (95:5) for 45 min. The resin was removed byfiltration and the filtrate was allowed to stand for an additional hour.The solution was concentrated to a residue. The crude peptide wasanalyzed by analytical HPLC (system A). Typical purity of the crudepeptide ranged from 80% to 95%. The peptides were purified bypreparative HPLC (system B) using an appropriate gradient (typically10-30%). Pure fractions were then lyophilized to provide the desiredpeptide as a white solid. Typical yields were 20-50% and a purity of96-99%.

[1251] Analytical HPLC Conditions (System A)

[1252] Column: Chromolith RP-18e 4.6 mm×100 mm from EM science

[1253] Gradient: 5-50% B in A over 6 min

[1254] Flow Rate: 4 mL/min

[1255] Solvent A: 0.1% TFA in water

[1256] Solvent B: 0.1% TFA in acetonitrile

[1257] Wavelength: 210 nm, 280 nm

[1258] Preparative HPLC Conditions (System B)

[1259] Column: Ultro 120 5 C18Q 150×20 mm from Peeke Scientific

[1260] Gradient: 0-20%, or 10-30% or 20-40% B in A over 40 min

[1261] Flow Rate: 18 mL/min

[1262] Solvent A: 0.1% TFA in water

[1263] Solvent B: acetonitrile

[1264] Wavelength: 214 nm

[1265] Step C: Coupling of Peptide acids to Doxorubicin

[1266] To a mixture of peptide acid (0.052 mmol, 1.2 equivalents),doxorubicin hydrochloride (0.043 mmol, 25 mg), and HATU (0.0604 mmol,22.9 mg, 1.4 equivalents) was added DMF (1 mL) then 2,6-lutidine (0.17mmol, 20 μL, 4 eqiuvalents). The mixture was mixed until a homogeneoussolution was obtained. After 4 to 24 hours (monitor by HPLC system A)the reaction was diluted with water (9 mL) and directly purified bypreparative HPLC (system D). Pure fractions were then lyophilized toprovide the desired peptide doxorubicin conjugate as a fluffy red solid.The quality of the final conjugate was verified by analytical HPLC(system C) and mass spectroscopy. Typical yields were 10-30% with apurity of 95-99%. (Note: when the peptide acid contained a histidineresidue DIEA was substituted as the base and the reaction time wasshortened to 1 hour).

[1267] Deprotection of fluorenylmethylesters of peptide doxorubicinconjugates: In cases where free carboxylic acid is present in theconjugate a fluorenyl methyl ester was used to protect a carboxylic acidduring coupling of the C-terminus of the peptide acid to doxorubicin,the flourenylmethyl group was subsequently removed with 10% morpholinein DMF for 1 hour.

[1268] Analytical HPLC Conditions (System C)

[1269] Column: Chromolith RP-18e 4.6 mm×100 mm from EM science

[1270] Gradient: 5-50% B in A over 6 min

[1271] Flow Rate: 4 mL/min

[1272] Solvent A: 0.1% TFA in water

[1273] Solvent B: 0.1% TFA in acetonitrile

[1274] Wavelength: 210 nm, 280 nm

[1275] Examples of retention times (min) Doxorubicin 4.05Ac-Gly-Ser-Gly-Arg-Ser-nLeu-Dox 4.34 MeOCO-Thr-Gly-Arg-Ser-nLeu-Dox 4.39PhSO2-Thr-Gly-Arg-Ser-nLeu-Dox 4.83N,N-dimethylglycine-Thr-Gly-Arg-Ser-nLeu-Dox 4.27Ac-Thr-Gly-Arg-Ser-nLeu-Dox 4.32

[1276] Preparative HPLC Conditions (System D)

[1277] Column: Ultro 120 5 C18Q 150×20 mm from Peeke Scientific

[1278] Gradient: 10-30% B in A over 40 min

[1279] Flow Rate: 18 mL/min

[1280] Solvent A: 0.1% acetic acid in water

[1281] Solvent B: acetonitrile

[1282] Wavelength: 214 nm

EXAMPLE 2 Preparation of Ac-Gly-Ser-Gly-Arg-Ser-nLeu-Dox

[1283] Step A: Manual Synthesis ofAc-Gly-Ser(tBu)-Gly-Arg(Pbf)-Ser(tBu)-nLeu-Wang Resin

[1284] In a 250 mL fritted peptide synthesis vessel equipped withnitrogen agitation and vacumm assisted drainage, Fmoc-nL-Wang resin(nova-biochem, 3.3 grams, 0.9 mmol/g, 3 mmol) was pre-swelled for 30 minusing DMF. The peptide was then elongated by repeating the 4 stepprocedure below a total of five times with the following Fmocaminoacids: Fmoc-Ser(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gly-OH,Fmoc-Ser(tBu)-OH, Fmoc-Gly-OH.

[1285] Iterative Coupling Procedure

[1286] 1. the resin was mixed with 20% piperdine in DMF (100 mL) for 5min then drained (repeat 3 times).

[1287] 2. the resin was agitated with DMF (100 mL) for 30 sec thendrained (repeat 3 times).

[1288] 3. to a mixture of Fmoc-aminoacid (12 mmol), HOBT (12 mmol, 4equivalents, 1.622 g), TBTU (11.7 mmol, 3.9 equivalents, 3.757 g), DMF(10 mL) and NMP (90 mL) was added DIEA (12 mmol, 4 equivalents, 2.10mL). After stirring for 5 min to allow pre-activation, the solution wasadded to the synthesis vessel. The reaction was checked for completionby ninhydrin test and then drained. (If the ninhydrid test was blue, adouble coupling (repeat step 3) was performed.

[1289] 4. the resin was agitated with DMF (100 mL) for 30 sec thendrained (repeat 3 times).

[1290] The elongated resin(Fmoc-Gly-Ser(tBu)-Gly-Arg(Pbf)-Ser(tBu)-nLeu-Wang resin) was treated tosteps 1 and 2 above to remove the Fmoc group. A solution of aceticanhydride (15 mmol, 5 equivalents, 1.42 mL), DIEA (15 mmol, 5equivalents, 2.62 mL), DMF (10 mL) and NMP (90 mL) was added to thereaction vessel. After 1 hour the resin was washed with DMF (100 mL, 3times), CH₂Cl₂ (100 mL, 3 times) and MeOH (100 mL, 3 times). The resinwas dried under vacuum for 15 hours.

[1291] Step B: Preparation of Ac-Gly-Ser-Gly-Arg-Ser-nLeu-OH

[1292] To the above synthesis vessel containingAc-Gly-Ser(tBu)-Gly-Arg(Pbf)-Ser(tBu)-nLeu-Wang resin (3 mmol) was addedTFA/H₂O (95:5, 50 mL). After gently agitation for 45 min the cleavagesolution was collected and the filtrate was allowed to stand for anadditional 90 min. The solution was concentrated to a residue. The crudepeptide was analyzed by analytical HPLC (system A, RT=1.73, purity=90%).The residue was dissolved in water (50 mL) and hexanes (10 mL) andmixed. The hexanes layer was removed and the aqueous layer bubbled withnitrogen to evaporate any remaining hexanes. The crude peptide waspurified by preparative HPLC (system E). Pure fractions were thenlyophilized to provide Ac-Gly-Ser-Gly-Arg-Ser-nLeu-OH (1.04 g, 1.68mmol, 56%) as a white solid. The purity was evaluated by analytical HPLC(system A, RT=1.73 min, 97% purity) and the constitution by massspectrospcopy (ion observed at 617.9).

[1293] Preparative HPLC Conditions (System E)

[1294] Column: Waters Delta-Pak radial compression column, 15 um, 100A

[1295] Gradient: 5-15% B in A over 40 min

[1296] Flow Rate: 80 mL/min

[1297] Solvent A: 0.1% acetic acid in water

[1298] Solvent B: acetonitrile

[1299] Wavelength: 214 nm

[1300] Step C: Preparation of Ac-Gly-Ser-Gly-Arg-Ser-nLeu-Dox

[1301] To a mixture of Ac-Gly-Ser-Gly-Arg-Ser-nLeu-OH (1.68 mmol, 1.04g, 1.1 equivalents), doxorubicin hydrochloride (1.53 mmol, 887.8 mg),and HATU (1.76 mmol, 669.6 mg, 1.15 equivalents) was added DMF (40 mL)then 2,6-lutidine (6.12 mmol, 709 μL, 4 eqiuvalents). The solution wasstirred for 18 hours. The reaction was diluted with water (100 mL),acidified with acetic acid (400 μL) and purified immediately in threebatches by preparative HPLC (system E). Each red colored fraction wasanalyzed by analytical HPLC (system F). Fractions of greater than 95%purity were then combined. The acetonitrile was removed under vacuum andthe remaining solution was lyophilized to provideAc-Gly-Ser-Gly-Arg-Ser-nLeu-Dox (0.682 mmol, 780 mg, 45%) as a fluffyred solid. The purity was evaluated by analytical HPLC (system F,RT=3.51 min, 95% purity) and the constitution by mass spectrospcopy (ionobserved at 1143.5).

[1302] Analytical HPLC Conditions (System F)

[1303] Column: Chromolith RP-18e 4.6 mm×100 mm from EM science

[1304] Gradient: 20-40% B in A over 6 min

[1305] Flow Rate: 4 mL/min

[1306] Solvent A: 0.1% TFA in water

[1307] Solvent B: 0.1% TFA in acetonitrile

[1308] Wavelength: 210 nm, 280 nm

[1309] Preparative HPLC Conditions (System E)

[1310] Column: Waters Delta-Pak radial compression column, 15 um, 100A

[1311] Gradient: 15-25% B in A over 40 min

[1312] Flow Rate: 80 mL/min

[1313] Solvent A: 0.1% acetic acid in water

[1314] Solvent B: acetonitrile

[1315] Wavelength: 214 nm

EXAMPLE 3 General Procedures for Preparing Peptide-Taxol Conjugates

[1316] Step A: Synthesis of Peptides on Wang Resin

[1317] See Example 1, Step A.

[1318] Step B: Cleavage of Peptides from Wang Resin

[1319] See Example 1, Step B.

[1320] Step C: Coupling of Peptide Acids to 7-Gly-Taxol or 7-Ala-Taxol

[1321] To a mixture of peptide acid (0.0121 mmol, 1.1 equivalents),7-Gly-Taxol of 7-Ala-Taxol (0.011 mmol), and HATU (0.0154 mmol, 5.9 mg,1.4 equivalents) was added DMF (0.3 mL) then 2,6-lutidine (0.044 mmol,5.1 μL, 4 eqiuvalents). The mixture was mixed until a homogeneoussolution was obtained. After 4 to 24 hours (monitor by HPLC system H)the reaction was diluted with water (9 mL) and directly purified bypreparative HPLC (system 1). Pure fractions were then lyophilized toprovide the desired peptide taxol conjugate as a fluffy white solid. Thequality of the final conjugate was verified by analytical HPLC (systemH) and mass spectroscopy. Typical yields were 30-50% with a purity of96-99%.

[1322] Analytical HPLC Conditions (System H)

[1323] Column: Chromolith RP-18e 4.6 mm×100 mm from EM science

[1324] Gradient: 5-90% B in A over 6 min

[1325] Flow Rate: 4 mL/min

[1326] Solvent A: 0.1% TFA in water

[1327] Solvent B: 0.1% TFA in acetonitrile

[1328] Wavelength: 210 nm, 280 nm

[1329] Examples of Retention Times (min) Ac-Gln-Ser-Arg-Ala-Ala-Taxol2.86 Ac-Gln-Ser-Arg-Ser-Ala-Ala-Taxol 2.79Ac-Ser-Gly-Arg-Ala-Ser-Ala-Taxol 2.87 Ac-Arg-Ser-Arg-Ala-Ala-Taxol 2.80Ac-Ser-Gly-Arg-Ser-Ser-Ala-Taxol 2.81

[1330] Preparative HPLC Conditions (System I)

[1331] Column: Ultro 120 5 C18Q 150×20 mm from Peeke Scientific

[1332] Gradient: 20-45% B in A over 40 min

[1333] Flow Rate: 18 mL/min

[1334] Solvent A: 0.1% TFA in water

[1335] Solvent B: acetonitrile

[1336] Wavelength: 214 nm

EXAMPLE 4 Preparation of N-Ac-Arg-Gln-Ser-Arg-Ala-Ala-DOX

[1337]

[1338] Step A: N-Ac-Arg-Gln-Ser-Arg-Ala-Ala-OH

[1339] Using the following general procedure, the N-acetyl peptidicsubstrate N-Ac-Arg-Gln-Ser-Arg-Ala-Ala-OH was synthesized in a peptidesynthesis flask. Commencing with commercial Fmoc-Ala-Wang resin (0.35 g,0.84 mmol, Nova), standard Fmoc-deprotection with 20% piperidine wasfollowed by a sequential iterative coupling-Fmoc deprotection strategy.Each coupling employed a 3-fold excess (2.52 mmol) of Fmoc-Ala,Fmoc-Arg(Boc)₂, Fmoc-Ser(tBu), Fmoc-Gln(Trt) and Fmoc-Arg(Boc)₂,respectively. Couplings were achieved using PyBOP (2.52 mmol) and DIEA(2.52 mmol) in DMF solvent. During each coupling cycle, the Fmocprotecting group was removed using 20% piperidine in DMF. After removalof the N-terminal Fmoc group, capping with acetic anhydride (1.43 mmol,1.7 equiv.), DMAP (0.25 mmol, 0.3 equiv.), and DIEA (1.26 mmole, 1.5equiv.) afforded the resin-bound N-acetyl intermediate. The protectedpeptide resin was treated with 50% TFA in methylene chloride for 30 minto cleave the Wang resin and then the Boc, Trt and t-Bu protectinggroups were removed with 70% TFA in methylene chloride. Solvent andother volatile byproducts were evaporated under reduced pressure and thecrude product was dissolved in water and lyophilized to afford the titlecompound as a nearly colorless, amorphous solid. Mass spectral analysisconfirmed the desired molecular weight. HPLC analysis indicated theproduct to be of approximately 95% purity. The peptide carboxylic acidintermediate can be further purified by trituration or by preparativeHPLC, if desired.

[1340] Step B: N-Ac-Arg-Gln-Ser-Arg-Ala-Ala-DOX

[1341] The intermediate from Step A (20 mg, 0.027 mmol) was dissolved indry DMF (0.8 mL) and was stirred at room temperature under a nitrogenatmosphere. To this solution was added doxorubicin hydrochloride (15.6mg, 0.027 mmol), EDC (6.8 mg, 0.035 mmol), HOAt (4.8 mg, 0.035 mmol) and2,6-lutidine (7.3 μL, 0.06 mmol). Stirring was continued untilcompletion of the coupling, as monitored by analytical HPLC (system J,see below). The solution was filtered and the crude product was purifiedby C18 RP-HPLC (A=0.1% AcOH/H₂O; B=CH₃CN), gradient elution 100% to 60%A over 60 min). Homogeneous product fractions (evaluated by HPLC, systemJ) were pooled and lyophilized to afford the title compound as a lightred solid.

[1342] HPLC conditions, System J:

[1343] Column: Phenomenex 15 cm #00F-3033-E0, C18

[1344] Eluant: Gradient 95:5 (A:B) to 25:75 (A:B) over 20 min.

[1345] A=0.1% TFA/H₂O, B=0.1% TFA/Acetonitrile

[1346] Flow: 1 mL/min.

[1347] Wavelength: 210 nm, 280 nm

[1348] Retention times: Doxorubicin=8.89 min.

[1349] N-Ac-Arg-Gln-Ser-Arg-Ala-Ala-Dox=8.4 min.

[1350] Physical Properties:

[1351] Molecular Formula: C₅₅H₇₈N₁₄O₂₀

[1352] Molecular Weight: 1255.3

[1353] Low Resolution Mass Spec: 628.2 (M+2/2)

[1354] Table 2 lists data for additional peptidic substrate-Doxorubicinconjugates. These conjugates were prepared from the appropriate aminoacid precursors that were elaborated by the general procedures describedin Example 4. TABLE 2 HPLC- Mass Retention Peptidic substrate-DOXConjugate Spectrum Time (min.) Acetyl-Arg-Arg-Gln-Ser-Arg-Ala-Ala-DOX471.2 8.23 (M + 3/3) Acetyl-Leu-Arg-Arg-Gln-Ser-Arg-Ala-Ala- 509.2 8.60DOX (M + 3/3)

EXAMPLE 5 Determination of Times to 50% Cleavage of Doxorubicin/PeptidicSubstrate Conjugates by the Recombinant Protease Domain of MTSP1

[1355] One millimolar stock solutions were prepared for each peptidicsubstrate conjugate in double distilled water. Cleavage reactions werethen performed in which 100 μM conjugate was mixed with 1 or 10 nM ofthe recombinantly-produced active single chain protease domain of MTSP1(residue 615-855 in SEQ ID No. 2, encoded by nucleotides 1865-2582 inSEQ ID No. 1) in 29.2 mM Tris, pH 8.4, 29.2 mM Imidazole, 217 mM NaCl.Final reaction volume was 200 μL. These reactions were incubated in awater bath at 37° C. At times ranging from 2 to 128 minutes, 20 μLsamples were removed, and enzymatic activity was stopped by the additionof trifluoroacetic acid to 0.33%. The amount of hydrolysis in eachsample was measured by reverse phase HPLC. Percent hydrolysis was thencalculated by dividing the area under the product peak by the sum of theareas under substrate and product peaks. Percent unhydrolyzed substratewas plotted against log of reaction times, and the plots were fit tosigmoidal curves using Prism software from Graphpad Inc. (San Diego,Calif.) to determine times at which 50% of each substrate was cleaved.

[1356] Results for certain of the conjugates provided herein are shownin FIG. 1 (conditions: 1 nM MTSP1 with 100 μM conjugate at 37° C. in 12mM tris(hydroxymethyl)aminomethane, pH 8.0, 25 mM NaCl, 0.5 mM CaCl₂;reactions were quenched with 0.33% trifluoroacetic acid).

EXAMPLE 6 In Vitro Assay of Cytotoxicity of Conjugates

[1357] The cytotoxicity of the conjugates also can be tested to confirmthat the conjugates act as prodrugs. The conjugates are tested against aline of cells, which is known to be killed by unmodified cytotoxicagent, using-an Alamar Blue assay. Cells, such as LNCaP cells (TheAmerican Type Culture Collection (Rockville, Md.)), that express a cellsurface protease, such as MTSP1 or endotheliase, are seeded in 96 wellplates at a density of 1×104 cells/well (0.1 mL/well). A platecontaining medium alone is used as a control. The cells are incubatedfor 3 days at 37° C. and 20 μL of Alamar Blue is added to the assaywell(s). After 7 h of incubation, cell killing is measured using anEL-310 plate reader at 570 and 600 nm. Values for cell killing areexpressed as the percentage reduction in cell numbers relative to themedia controls.

EXAMPLE 7 In Vivo Efficacy of Conjugates

[1358] Tumor cells are trypsinized, resuspended in the growth medium andcentrifuged for 6 min at 200×g. The cells are resuspended in serum-freeα-MEM and counted. The appropriate volume of this solution containingthe desired number of cells is then transferred to a conical centrifugetube, centrifuged as before and resuspended in the appropriate volume ofa cold 1:1 mixture of α-MEM-Matrigel. The suspension is kept on iceuntil the animals are inoculated.

[1359] Male nude mice 10 weeks of age are used. Mice are individuallyweighed and assigned to groups (n=10 per group) with no more than a2-gram difference in weight between individual mice within each group.On day 1, mice are inoculated subcutaneously with the tumor cell line.ach mouse is inoculated with, for example, 0.5 mL of 0.5×10⁶ to 10⁸tumor cells/mL in a 60% solution of ice-cold Matrigel and α-MEM. Then,24 h later, conjugate administration began. Vehicle-treated mice areinjected with 5% dextrose in water. At the end of a predetermined time,such as 18 days to two months or more, the mice are sacrificed, andtumor size and mass or other parameters are measured. Tumor size andmass or the other parameters for conjugate-treated mice are compared tovehicle-treated mice to determine efficacy of the conjugate.

[1360] Following inoculation with the tumor cells the mice are treatedunder one of three protocols:

[1361] Protocol A

[1362] One day after cell inoculation the animals are dosed with 1 to100, or 3 to 50, or 5 to 25, or 7 to 22 μmol/kg, including 7.2 or 17.9μmol/kg, of test conjugate, unmodified cytotoxic agent or vehiclecontrol (sterile water). Dosages of the conjugate and cytotoxic agentare initially the maximum non-lethal amount, but can be subsequentlytitrated lower. Identical doses are administered at 24 hour intervalsfor 5 days. At the end of 5.5 weeks or other suitable interval, the miceare sacrificed and weights of any tumors present are measured. Theanimals' weights are determined at the beginning and end of the assay.

[1363] Protocol B At 14-15 days after cell inoculation, the animals aredosed with 1 to 100, or 3 to 50, or 5 to 25, or 7 to 22 μmol/kg,including 7.2 or 17.9 μmol/kg, of test conjugate, unmodified cytotoxicagent, or vehicle control (sterile water). Dosages of the conjugate andcytotoxic agent are initially the maximum non-lethal amount, but can besubsequently titrated lower. Identical doses are administered at 24 hourintervals for 5 days. At the end of 5.5 weeks or other suitableinterval, the mice are sacrificed and weights of any tumors present aremeasured. The animals' weights are determined at the beginning and endof the assay.

[1364] Protocol C

[1365] One day after cell inoculation, the animals are dosed byinterperitoneal administration with 1 to 100, or 3 to 50, or 5 to 25, or7 to 22 μmol/kg, including 7.2 or 17.9 μmol/kg, of test conjugate,unmodified cytotoxic agent, or vehicle control (sterile water). Dosagesof the conjugate and cytotoxic agent are initially the maximumnon-lethal amount, but can be subsequently titrated lower. Identicaldoses are administered at 7 day intervals for 5 weeks. At the end of 5.5weeks or other suitable interval, the mice are sacrificed and weights ofany tumors present are measured. The animals' weights are determined atthe beginning and end of the assay.

EXAMPLE 8 Gene Expression Profiles of Exemplary MTSPs and DomainOrganization

[1366] Gene Expression Profile of MTSP1 in Normal Tissues, Cancer Cellsand Cancer Tissues

[1367] To obtain information regarding the tissue distribution and geneexpression level of MTSP1, the DNA insert from a Pichia pastorisexpression vector, pPIC9K-MTSP1, containing the encoding nucleic acid,was used to probe a blot containing RNA from 76 different human tissues(catalog number 7775-1; human multiple tissue expression (MTE) array;CLONTECH, Palo Alto, Calif.). Significant expression was observed in thecolon (ascending, transverse and descending), rectum, trachea, esophagusand duodenum. Moderate expression levels were observed in the jejunum,ileum, ilocecum, stomach, prostate, pituitary gland, appendix, kidney,lung, placenta, pancreas, thyroid gland, salivary gland, mammary gland,fetal kidney, and fetal lung. Lower expression levels were seen in thespleen, thymus, peripheral blood leukocyte, lymph node, bone marrow,bladder, uterus, liver, adrenal gland, fetal heart, fetal liver, fetalspleen, and fetal thymus. A significant amount of the MTSP1 transcriptwas also detected in colorectal adenocarcinoma cell line (SW480),Burkitt's lymphoma cell line (Daudi), and leukemia cell line (HL-60).RT-PCR of the MTSP1 transcript in several human primary tumorsxenografted in athymic nude mice was performed using gene-specificprimers. A high level of MTSP1 transcript was detected in colonadenocarcinoma (CX-1) and pancreatic adenocarcinoma (GI-103). Moderatelevels were observed in another colon adenocarcinoma (GI-112), ovariancarcinoma (GI-102), lung carcinoma (LX-1), and breast carcinoma(GI-101). Another lung carcinoma (GI-117) expressed a low level of theMTSP1 transcript. A similar RT-PCR was performed to detect the presenceof the MTSP1 transcript in PC-3 and LNCaP cell lines. Both cell linesexpressed significant amounts of MTSP1 transcript. MTSP1 also is amarker for ovarian cancer.

[1368] Gene Expression Profile of the Serine Protease MTSP3 in Normaland Tumor Tissues

[1369] To obtain information regarding the tissue distribution of theMTSP3 transcripts, the DNA insert encoding the MTSP3 protease domain wasused to probe a RNA blot composed of 76 different human tissues (catalognumber 7775-1; human multiple tissue expression (MTE) array; CLONTECH,Palo Alto, Calif.). The expression pattern observed in decreasing signallevel was: trachea=colon (descending)=esophagus>colon (ascending)>colon(transverse)=rectum>ileum>duodenum>jejunum>bladder>ilocecum>stomach>kidney>appendix.It also is expressed less abundantly in fetal kidney, and in two tumorcell lines, HeLa S3 and leukemia, K-562. Northern analysis using RNAblots (catalog numbers 7780-1, 7765-1 & 7782-1; human 12-lane, humanmuscle and human digestive system multiple tissue northern (MTN) blots;CLONTECH) confirmed that the expression was detected most abundantly inthe colon, moderately in the esophagus, small intestine, bladder andkidney, and less abundantly in stomach and rectum. A single transcriptof ˜2.2 kb was detected.

[1370] Amplification of the MTSP3 transcript in several human primarytumors xenografted in mouse was performed using gene-specific primers.The MTSP3 transcript was detected in lung carcinoma (LX-1), colonadenocarcinoma (CX-1), colon adenocarcinoma (GI-112) and ovariancarcinoma (GI-102). No apparent signal was detected in another form oflung carcinoma (GI-117), breast carcinoma (GI-101), pancreaticadenocarcinoma (GI-103) and prostatic adenocarcinoma (PC3).

[1371] Gene Expression Profile of MTSP4 in Normal and Tumor Tissues

[1372] To obtain information regarding the gene expression profile ofthe MTSP4 transcript, a DNA fragment encoding part of the LDL receptordomain and the protease domain was used to probe an RNA blot composed of76 different human tissues (catalog number 7775-1; human multiple tissueexpression (MTE) array; CLONTECH). As in the northern analysis of gelblot, a very strong signal was observed in the liver. Signals in othertissues were observed in (decreasing signal level): fetalliver>heart=kidney=adrenal gland=testis fetal heart and kidney=skeletalmuscle=bladder=placenta>brain spinal cord=colon=stomach=spleen=lymphnode=bone marrow=trachea=uterus=pancreas=salivary gland=mammarygland=lung. MTSP4 also is expressed less abundantly in several tumorcell lines including HeLa S3=leukemia K-562=Burkitt's lymphomas (Rajiand Daudi)=colorectal adenocarcinoma (SW480)>lung carcinoma(A549)=leukemia MOLT-4=leukemia HL-60. PCR of the MTSP4 transcript fromcDNA libraries made from several human primary tumors xenografted innude mice (human tumor multiple tissue cDNA panel, catalog numberK1522-1, CLONTECH) was performed using MTSP4-specific primers. The MTSP4transcript was detected in breast carcinoma (GI-101), lung carcinoma(LX-1), colon adenocarcinoma (GI-112) and pancreatic adenocarcinoma(GI-103). No apparent signal was detected in another form of lungcarcinoma (GI-117), colon adenocarcinoma (CX-1), ovarian carcinoma(GI-102). and prostatic adenocarcinoma (PC3). The MTSP4 transcript wasalso detected in LNCaP and PC-3 prostate cancer cell lines as well as inHT-1080 human fibrosarcoma cell line.

[1373] Gene Expression Profile of MTSP6 in Normal and Tumor Tissues

[1374] To obtain information regarding the gene expression profile ofthe MTSP6 transcript, a 495 bp DNA fragment obtained from PCR reactionwith primers Ch 17-NSP-3 and NSP-4AS was used to probe an RNA blotcomposed of 76 different human tissues (catalog number 7775-1; humanmultiple tissue expression (MTE) array; CLONTECH). The strongest signalwas observed in duodenum. Signals in other tissues were observed in(decreased signal level): Stomach>trachea=mammary gland=thyroidgland=salivary gland=pituitarygland=pancreas>kidney>lung>jejunum=ileum=ilocecum=appendix=fetalkidney>fetal lung. Very weak signals also can be detected in severalother tissues. MTSP6 also is expressed in several tumor cell linesincluding HeLa S3>colorectal adenocarcinoma (SW480)>leukemiaMOLT-4>leukemia K-562. PCR analysis of the MTSP6 transcript from cDNAlibraries made from several human primary tumors xenografted in nudemice (human tumor multiple tissue cDNA panel, catalog number K1522-1,CLONTECH) was performed using MTSP6-specific primers (Ch17-NSP-3 andCh17-NSP2AS). The MTSP6 transcript was strongly detected in lungcarcinoma (LX-1), moderately detected in pancreatic adenocarcinoma(GI-103), weakly detected in ovarian carcinoma (GI-102); and very weaklydetected in colon adenocarcinoma (GI-112 and CX-1), breast carcinoma(GI-101), lung carcinoma (GI-117) and prostatic adenocarcinoma (PC3).The MTSP6 transcript was also detected in breast cancer cell lineMDA-MB-231, prostate cancer cell line PC-3, but not in HT-1080 humanfibrosarcoma cell line. MTSP6 also is expressed in mammary glandcarcinoma cDNA (Clontech).

[1375] Gene Expression Profile of MTSP9 in Normal, Tumor Tissues andCell Lines

[1376] To obtain a gene expression profile of the MTSP9 transcript, theMTSP9 cDNA fragment obtained from human pancreas was used to probe a dotblot composed of RNA extracted from 76 different human tissues (HumanMultiple Tissue Expression (MTE) Array; Clontech, Palo Alto, Calif.;catalog no. 7775-1). The results of this analysis indicate that MTSP9 ishighly expressed in the esophagus and expressed at a low level in manyother tissues. The MTSP9 transcript is found in kidney (adult andfetal), spleen (adult and fetal), placenta, liver (adult and fetal),thymus, peripheral blood leukocyte, lung (adult and fetal), pancreas,lymph node, bone marrow, trachea, uterus, prostate, esophagus, testes,ovary and the gland organs (mammary, adrenal, thyroid, pituitary andsalivary). MTSP9 also is expressed in tumor esophagus tissues, in a lungcarcinoma (A549 cell line) and, at a low level, in a colorectalcarcinoma (SW480), lymphoma (Raji and Daudi), a cervical carcinoma(HeLaS3) and leukemia (HL-60, K-562 and MOLT-4) cell lines.

[1377] Gene Expression Profile of MTSP10 in Normal and Tumor Tissues

[1378] To obtain information regarding the gene expression profile ofthe MTSP10 transcript, PCR analysis was carried out on cDNA panels madefrom several human adult tissues (Clontech, Cat. #K1420-1) cDNA panelusing MTSP10-specific primers. MTSP10 transcript was detected inpancreas, lung and kidney. MTSP10 transcript was also detected in smallintestine Marathon-Ready cDNA (Clontech). PCR of the MTSP10 transcriptfrom cDNA libraries made from several human primary tumors xenograftedin nude mice (human tumor multiple tissue cDNA panel, catalog numberK1522-1, CLONTECH) was also performed. The MTSP10 transcript wasdetected in breast carcinoma (GI-101), lung carcinoma (LX-1 and GI-117),ovarian carcinoma (GI-102), and pancreatic adenocarcinoma (GI-103). TheMTSP10 transcript can be weakly detected in prostatic adenocarcinoma(PC3). No apparent signal was detected in two forms of colonadenocarcinomas (GI-112 and CX-1). The MTSP10 transcript was alsodetected in CWR22R prostate tumor grown on nude mice.

[1379] Domain Organization and Gene Expression Profile of MTSP12 inNormal and Tumor Tissues

[1380] Domain Organization of MTSP12PD1, -PD2 and -PD3 and Homology toother Serine Proteases

[1381] Sequence and protein domain analyses of the translated MTSP12PD1,-PD2 and -PD3 nucleotide sequences indicate that these three serineproteases are contiguous. The sequence order is as follows: MTSP12-PD1is found at the N terminus followed by MTSP12-PD2, and MTSP12-PD3 is atthe C terminus. MTSP12-PD1 and -PD2 contain a trypsin-like serineprotease domain (aa 236 to aa 465 and aa 537 to aa 765 for MTSP12-PD1and -PD2, respectively) characterized by the presence of a proteaseactivation cleavage site ( . . . R₂₃₆↓I₂₃₇VGGMEAS . . . , and . . .R₅₃₇↓V₅₃₈VGGFGAA . . . , for MTSP12-PD1 and -PD2, respectively, andwhere ¦ indicates a protease activation cleavage site) and the catalytictriad residues (His₂₇₇, Asp₃₂₆ and Ser₄₂₁ in MTSP12-PD1; His₅₇₈, Asp₆₂₆and Ser₇₂₁ in MTSP12-PD2) in 3 highly-conserved regions of the catalyticdomain. MTSP12-PD3 contains a serine protease domain (aa 861 to aa1087); it has a protease activation cleavage site ( . . .R₈₆₀↓I₈₆₁VGGSAAG . . . ) and has the catalytic His₉₀₂ and Asp₉₄₉, but ithas a Ala₁₀₄₃ instead of the conserved catalytic serine found in serineproteases. Several domains are found upstream of the MTSP12-PD1 serineprotease domain and these include a transmembrane domain (aa 28 to aa50), a SEA (sea urchin sperm protein-enterokinase-agrin) domain (aa 51to aa 170) and an LDLa (low density lipoprotein receptor class a) domain(aa 187 to aa 225). There are 5 possible N-linked glycosylation sites(N₁₁₆SS, N₅₈₁HT, N₆₇₂AT, N₆₉₇FS and N₈₂₀ST). In the protease domain ofMTSP12-PD1, there is an unpaired cysteine (C₃₄₆) in a single chain formof the protease domain and the following Cys pairings are noted:C₂₆₂-C₂₇₈; C₃₆₀-C₄₂₇; C₄₁₇-C₄₄₆; C₃₉₂-C₄₀₆. In the protease domain ofMTSP12-PD2, there is an unpaired cysteine (C₆₄₆) in a single chain formof the protease domain, and the following Cys pairings are noted:C₅₆₃-C₅₇₉; C₆₆₀-C₇₂₇; C₆₉₂-C₇₀₆; C₇₁₇-C₇₄₆. In the protease domain ofMTSP12-PD3, there is an unpaired cysteine (C₉₆₉) in a single chain formof the protease domain, and the following Cys pairings are noted:C₈₈₇-C₉₀₃; C₉₈₃-C₁₀₄₉; C₁₀₁₄-C₁₀₂₈; C₁₀₃₉-C₁₀₆₈.

[1382] Alignment (blastp; http://www.ncbi.nlm.nih.gov/BLAST) of therespective MTSP12-PD1, MTSP12-PD2 and MTSP12-PD3 protein sequences toknown serine proteases deposited in the public database showed a 45%,45% and 48% identity to matriptase, a 44%, 43% and 41% identity withDESC1/endotheliase 1, a 44%, 43% and 48% identity to prostamin(AB030036), a 43%, 39% and 39% identity to spinesin (TMPRSS5;NM_(—)030770), and a 40%, 38% and 38% identity to marapsin(NM_(—)031948). The clone has about 93% homology at the nucleotide andencoded protein levels to a clone and encoded provided described inInternational PCT application No. WO 02/00860 (see SEQ ID Nos. 38 and 97therein). The encoded protein described in the PCT application, however,includes the Sequence set forth in SEQ ID No. 271 between amino acidsLeu373 and Val374 of SEQ ID No. 20, as well as an additional extendedsequence of amino acids beteween amino acids Ala48 and Phe49 of SEQ IDNo. 20 and lacks amino acids 91-124 of SEQ ID No. 20. The proteinprovided in International PCT application No. WO02/00860 can be used inthe methods provided herein.

[1383] Gene and Tissue Expression Profile of MTSP12

[1384] To obtain information regarding the tissue distribution profileof the MTSP12PD1, -PD2 and -PD3 transcripts, 3 cDNA probes wereprepared. Data indicate that the MTSP12PD1, -PD2 and -PD3 transcript isexpressed at a low level in most of the 76 tissues and cell lines, butat a higher level in the lymph node and testes.

[1385] To compare the expression profile of MTSP12PD1, -PD2 and -PD3 ina range of normal human and matched tumor tissues, a matchedtumor/normal expression array (catalog number 7840-1;http://www.clontech.com) composed of 68 paired cDNA samples fromindividual patients was used. Results show that the MTSP12PD1, -PD2 and-PD3 transcript is expressed at a low level in a number of normaltissues including breast, uterus, colon, ovary, lung, kidney and rectum,but is not differentially expressed in any of the matched tumors. Italso is expressed at a low level in several tumor cell lines, includingHeLa (cervical carcinoma), Daudi (Burkitt's lymphoma), K562 (chronicmyelogenous leukemia), HL-60 (premyelocytic leukemia), G361 (melanoma),A549 (lung carcinoma), MOLT-4 (lymphoblastic leukemia), SW480(colorectal adenocarcinoma), and Raji (Burkitt's lymphoma).

[1386] Several SMART™ 5′-RACE cDNA libraries (catalog number K1811-1;http://www.clontech.com) prepared from normal breast, normal testes,normal prostate, prostate cancer cell lines and breast cancer cell lineswere analyzed for the presence of MTSP12PD1, -PD2 and -PD3 transcript byRT-PCR using two sets of gene-specific primers. The MTSP12-PD2 and -PD3transcript was detected in normal prostate, PC-3, LNCaP, normal breast,MDA-MB-231, MDA-MB-361, MDA-MB-453 and DU4475, but higher levels wereobserved in normal breast and MDA-MB-231. The MTSP12-PD1 transcript wasdetected in the same tissues and cell lines, except higher levels wereobserved in normal breast, MDA-MB-231 and DU4475.

[1387] Gene Expression Profile of MTSP20 in Normal, Tumor Tissues andCell Lines

[1388] To obtain information regarding the gene expression profile ofthe MTSP20 transcript, the MTSP20 cDNA fragment obtained from human lungtissue was used to probe a dot blot composed of RNA extracted from 76different human tissues (Human Multiple Tissue Expression (MTE) Array;Clontech, Palo Alto, Calif.; catalog no. 7775-1). The results indicatethat RNA encoding MTSP20 is expressed in a variety of tissues. TheMTSP20 transcript is found in liver, lymph node, cerebellum, pancreas,prostate, uterus, testis, glands (adrenal, thyroid and salivary),thymus, kidney and spleen. Lower transcript level can be found in lung,placenta, bladder, ovary, digestive system, circulatory system and otherparts of the the brain. MTSP20 is also expressed in certain tumor celllines including lung carcinoma (A519), colorectal carcinoma (SW480),lymphoma (Raji and Daudi), cervical carcinoma (HeLaS3) and leukemia(HL-60, K-562 and MOLT-4) cell lines.

[1389] Gene Expression Profile of MTSP22 in Normal, Tumor Tissues andCell Lines

[1390] MTSP22 is expressed in the uterine tissue, thymus, adiposetissue, and lymph node. It may also be expressed in lung, stomach,uterine, breast, ovarian, prostate and in other tumors. To obtaininformation regarding the gene expression profile of the MTSP22transcript, the cDNA fragment encoding the entire serine protease domainwas used to probe a dot blot composed of RNA extracted from 72 differenthuman tissues (Human Multiple Tissue Expression (MTE) Array; Clontech,Palo Alto, Calif.; catalog no. 7776-1) as well as a dot blot composed ofnormalized cDNA from 241 tumor and corresponding normal tissues fromindividual patients (Cancer Profiling Array, Clontech, catalog no.7841-1). The results of MTE analysis indicated that MTSP22 transcript isexpressed primarily in the esophagus. In the cancer profiling arrayanalysis, MTSP22 is highly expressed in 3 of the 42 normal uterus tissuesamples, but not in their matched tumor samples. In one of the 42 uterussamples, MTSP22 is expressed in tumor and its metastatic tissues, butnot in the normal tissue counterpart. MTSP22 is also expressed in 2 ofthe 17 stomach tumors and 2 of the 21 lung tumors, but not in theirnormal tissue counterparts. MTSP22 is also expressed in the normaltissue of the only pancreas matched cDNA pair. PCR analysis was alsoperformed using commercially available cDNA panel from several humanadult tissues (Clontech, Cat. #K1420-1 and K1420-2) and primary tumors(Clontech Cat. #K1522-1) as well as several Marathon-Ready cDNAs(Clontech).

[1391] MTSP22 cDNA was detected in thymus, adipose tissue, and lymphnode. Serine protease domain of MTSP22 and homology to other proteases.

[1392] Sequence analysis of the translated MTSP22 protease domainsequence revealed that MTSP22 contains a trypsin-like serine proteasedomain characterized by the presence of a protease activation cleavagesite at the amino terminus of the domain and the catalytic triadresidues (histidine, aspartate and serine) in three highly-conservedregions. Alignment of the protein sequence with that of endotheliase 1(same as serine protease DESC1 protein; GenBank accession numberAF064819) indicated that the two proteins share 50% sequence identity intheir protease domains.

[1393] Gene Expression Profile of MTSP25 in Normal, Tumor Tissues andCell Lines

[1394] MTSP25 is expressed in breast, colon, uterine, ovarian, kidney,prostate, testicular cancer tissue. It may also be expressed in lung,stomach, prostate and in other tumors. To obtain information regardingthe gene expression profile of the MTSP25 transcript, a 369 bp DNAfragment containing MTSP25 protease domain sequence (obtained from a PCRreaction) was used to probe a dot blot composed of RNA extracted from 72different human tissues (Human Multiple Tissue Expression (MTE) Array;Clontech, Palo Alto, Calif.; catalog no. 7776-1) as well as a dot blotcomposed of normalized cDNA from 241 tumor and corresponding normaltissues from individual patients (Cancer Profiling Array, Clontech,catalog no. 7841-1). The results of MTE analysis indicate that MTSP25transcript is expressed weakly in the lymph node. In the cancerprofiling array analysis, MTSP25 is highly expressed in all 4 prostatesamples (in normal and cancer samples). In one of the 20 kidney cDNApairs, MTSP25 is highly expressed in the tumor sample, but not in itsnormal tissue counterpart. MTSP25 is also expressed in 1 of the 50breast cancer samples, but not in its normal tissue counterpart.

[1395] MTSP25 is also expressed in 3 of the 42 normal uterus samples,but not in their tumor counterparts. MTSP25 expression is also detectedin 3 of the 14 ovarian cancer samples. Among these three samples, theexpression of MTSP25 was also detected in one of the matched normaltissue counterparts. MTSP25 expression was also detected in 5 tumorsamples in the 34 colon cDNA pairs.

[1396] PCR analysis was also performed using a commercially availablecDNA panel from several human adult tissues (Clontech, Cat. #K1420-1 andK1420-2) as well as several Marathon-Ready cDNAs (Clontech). MTSP25 cDNAwas strongly detected in testis and mammary gland adenocarcinoma, weaklydetected in brain, placenta, lung, spleen, prostate, small intestine,colon, and leukocyte, and very weakly detected in heart, liver, andpancreas.

EXAMPLE 9

[1397] Conjugates that have been prepared according to the procedures ofExamples 1-4 by routine and minor modification of the procedures, suchas using different Fmoc-amino acid building blocks, include:

[1398] Ac-R-Q-G-R-S-L-(Dox) (SEQ ID NO: 491);

[1399] Ac-R-Q-G-R-S-S-L-(Dox) (SEQ ID NO: 492);

[1400] Ac-R-Q-G-R-S-nL-(Dox) (SEQ ID NO: 493);

[1401] Ac-R-Q-G-R-S-nV-(Dox) (SEQ ID NO: 494);

[1402] Ac-R-Q-G-R-S-F-(Dox) (SEQ ID NO: 495);

[1403] Ac-R-Q-G-R-A-L-(Dox) (SEQ ID NO: 496);

[1404] Ac-R-Q-G-R-A-L-(Dox) (SEQ ID NO: 497);

[1405] Ac-R-Q-G-R-A-nL-(Dox) (SEQ ID NO: 498);

[1406] Ac-R-Q-G-R-A-nL-(Dox) (SEQ ID NO: 499);

[1407] Ac-R-Q-G-R-A-nV-(Dox) (SEQ ID NO: 500);

[1408] Ac-R-Q-G-R-A-Cha-(Dox) (SEQ ID NO: 501);

[1409] Ac-R-Q-G-R-A-F-(Dox) (SEQ ID NO: 502);

[1410] Ac-R-N-G-R-S-L-(Dox) (SEQ ID NO: 503);

[1411] Ac-R-N-G-R-A-nL-(Dox) (SEQ ID NO: 504);

[1412] Ac-R-Q-A-R-S-L-(Dox) (SEQ ID NO: 505);

[1413] Ac-R-Q-A-R-S-nL-(Dox) (SEQ ID NO: 506);

[1414] Ac-R-Q-A-R-S-nV-(Dox) (SEQ ID NO: 507);

[1415] Ac-R-Q-A-A-S-Cha-(Dox) (SEQ ID NO: 508);

[1416] Ac-R-Q-A-R-S-S-Cha-(Dox) (SEQ ID NO: 509);

[1417] Ac-R-Q-A-R-T-nL-(Dox) (SEQ ID NO: 510);

[1418] Ac-R-Q-A-R-A-L-(Dox) (SEQ ID NO: 511);

[1419] Ac-R-Q-A-R-A-nL-(Dox) (SEQ ID NO: 513);

[1420] Ac-R-Q-A-R-A-nV-(Dox) (SEQ ID NO: 514);

[1421] Ac-R-Q-A-R-A-Cha-(Dox) (SEQ ID NO: 515);

[1422] Ac-R-Q-S-R-A-A-(Dox) (SEQ ID NO: 516);

[1423] Ac-R-Q-S-R-A-(Dox) (SEQ ID NO: 517);

[1424] Ac-R-Q-S-R-A-nL-(Dox) (SEQ ID NO: 518);

[1425] Ac-R-Q-S-R-A-L-(Dox) (SEQ ID NO: 519);

[1426] Ac-R-Q-S-R-A-nV-(Dox) (SEQ ID NO: 520);

[1427] Ac-R-Q-S-R-A-Cha-(Dox) (SEQ ID NO: 521);

[1428] Ac-R-Q-S-R-S-S-L-(Dox) (SEQ ID NO: 522);

[1429] Ac-R-Q-S-R-S-L-(Dox) (SEQ ID NO: 523);

[1430] Ac-R-Q-S-R-S-dnL-(Dox) (SEQ ID NO: 524);

[1431] Ac-R-Q-S-R-S-nL-(Dox) (SEQ ID NO: 525);

[1432] Ac-R-Q-S-R-S-nV-(Dox) (SEQ ID NO: 526);

[1433] Ac-R-Q-S-R-S-allylG-(Dox) (SEQ ID NO: 527);

[1434] Ac-R-Q-S-R-S-Cha-(Dox) (SEQ ID NO: 528);

[1435] Ac-R-Q-S-R-T-nL-(Dox) (SEQ ID NO: 529);

[1436] Ac-R-Q-T-R-S-S-L-(Dox) (SEQ ID NO: 530);

[1437] Ac-R-Q-T-R-S-L-(Dox) (SEQ ID NO: 531);

[1438] Ac-R-N-S-R-S-nL-(Dox) (SEQ ID NO: 532);

[1439] Ac-R-Q-F-R-S-L-(Dox) (SEQ ID NO: 533);

[1440] Ac-R-Q-F-R-S-nL-(Dox) (SEQ ID NO: 534);

[1441] Ac-R-Q-F-R-S-nV-(Dox) (SEQ ID NO: 535);

[1442] Ac-R-Q-F-R-S-nL-(Dox) (SEQ ID NO: 536);

[1443] Ac-R-Q-F-R-S-Cha-(Dox) (SEQ ID NO: 537);

[1444] Ac-R-Q-F-R-A-L-(Dox) (SEQ ID NO: 538);

[1445] Ac-R-Q-F-R-A-nL-(Dox) (SEQ ID NO: 539);

[1446] Ac-R-Q-F-R-A-nV-(Dox) (SEQ ID NO: 540);

[1447] Ac-R-Q-F-R-A-Cha-(Dox) (SEQ ID NO: 541);

[1448] Ac-Q-S-R-S-S-nL-(Dox) (SEQ ID NO: 542);

[1449] MeOCO-Quat2-G-R-S-L-NH2 (SEQ ID NO: 483);

[1450] MeOCO-Quat3-G-R-S-L-NH2 (SEQ ID NO: 484);

[1451] MeOCO-Quat-G-R-S-L-NH2 (SEQ ID NO: 485);

[1452] MeOCO-Quat4-G-R-S-L-NH2 (SEQ ID NO: 486);

[1453] MeOCO-Quat5-G-R-S-L-NH2 (SEQ ID NO: 487);

[1454] MeOCO-Quat2-G-R-S-S-L-NH2 (SEQ ID NO: 488);

[1455] MeOCO-Quat4-G-R-S-L-(Dox) (SEQ ID NO: 489);

[1456] MeOCO-Quat2-G-R-S-L-(Dox) (SEQ ID NO: 490);

[1457] Ac-Q-G-R-S-L-(Dox) (SEQ ID NO: 445);

[1458] Ac-Q-G-R-S-S-L-(Dox) (SEQ ID NO: 446);

[1459] Ac-Q-G-R-A-S-L-(Dox) (SEQ ID NO: 447);

[1460] Ac-N-G-R-S-S-L-(Dox) (SEQ ID NO: 448);

[1461] Ac-Q-G-R-S-S-nL-(Dox) (SEQ ID NO: 449);

[1462] Ac-Q-G-R-S-S-nV-(Dox) (SEQ ID NO: 450);

[1463] Ac-Q-G-R-S-S-Cha-(Dox) (SEQ ID NO: 451);

[1464] Ac-Q-G-R-S-S-allylG-(Dox) (SEQ ID NO: 452);

[1465] Ac-Q-G-R-S-S-allylG-(Dox) (SEQ ID NO: 453);

[1466] Ac-Q-A-R-S-L-(Dox) (SEQ ID NO: 454);

[1467] Ac-Q-A-R-S-S-L-(Dox) (SEQ ID NO: 455);

[1468] Ac-Q-S-R-S-L-(Dox) (SEQ ID NO: 456);

[1469] Ac-Q-S-R-S-S-nV-(Dox) (SEQ ID NO: 457);

[1470] Ac-Q-S-R-S-S-Cha-(Dox) (SEQ ID NO: 458);

[1471] Ac-Q-S-R-S-S-L-(Dox) (SEQ ID NO: 459);

[1472] Ac-Q-T-R-S-S-L-(Dox) (SEQ ID NO: 460);

[1473] Ac-Q-Aib-R-S-S-Cha-(Dox) (SEQ ID NO: 461);

[1474] Ac-Q-Aib-R-S-S-L-(Dox) (SEQ ID NO: 462);

[1475] Ac-Q-Abu-R-S-S-Cha-(Dox) (SEQ ID NO: 463);

[1476] Ac-Q-Abu-R-S-S-L-(Dox) (SEQ ID NO: 464);

[1477] Ac-Q-Cha-R-S-S-Cha-(Dox) (SEQ ID NO: 465);

[1478] Ac-Q-F-R-S-L-(Dox) (SEQ ID NO: 466);

[1479] Ac-Q-F-R-S-S-L-(Dox) (SEQ ID NO: 467);

[1480] Ac-Q-Y-R-S-S-L-(Dox) (SEQ ID NO: 468);

[1481] Ac-R-G-R-S-L-(Dox) (SEQ ID NO: 469);

[1482] Ac-R-G-R-S-S-L-(Dox) (SEQ ID NO: 470);

[1483] Ac-R-G-R-S-S-Cha-(Dox) (SEQ ID NO: 471);

[1484] Ac-R-G-R-S-Cha-(Dox) (SEQ ID NO: 472);

[1485] Ac-R-A-R-S-L-(Dox) (SEQ ID NO: 473);

[1486] Ac-R-A-R-S-S-L-(Dox) (SEQ ID NO: 474);

[1487] Ac-R-S-R-S-L-(Dox) (SEQ ID NO: 475);

[1488] Ac-R-S-R-S-S-L-(Dox) (SEQ ID NO: 476);

[1489] Ac-R-S-R-S-Cha-(Dox) (SEQ ID NO: 477);

[1490] Ac-R-S-R-S-S-Cha-(Dox) (SEQ ID NO: 478);

[1491] Ac-R-F-R-S-L-(Dox) (SEQ ID NO: 479);

[1492] Ac-R-F-R-S-Cha-(Dox) (SEQ ID NO: 480);

[1493] Ac-Y-G-R-S-S-L-(Dox) (SEQ ID NO: 481);

[1494] Ac-M(O2)-S-R-S-L-(Dox) (SEQ ID NO: 482);

[1495] Ac-R-R-Q-S-R-A-A-(Dox) (SEQ ID NO: 105);

[1496] Ac-R-R-Q-S-R-I-(Dox) (SEQ ID NO: 610);

[1497] Ac-R-R-Q-S-R-S-S-L-(Dox) (SEQ ID NO: 543);

[1498] Ac-R-R-Q-S-R-S-L-(Dox) (SEQ ID NO: 544);

[1499] Ac-R-G-S-G-R-S-L-(Dox) (SEQ ID NO: 545);

[1500] Ac-R-G-S-G-R--S-nL-(Dox) (SEQ ID NO: 546);

[1501] Ac-R-G-S-G-R-A-nL-(Dox) (SEQ ID NO: 547);

[1502] Ac-R-G-S-G-R-S-S-L-(Dox) (SEQ ID NO: 548);

[1503] Ac-I-V-S-G-R-A-S-L-(Dox) (SEQ ID NO: 549);

[1504] Ac-R-R-Q-S-R-A-(Dox) (SEQ ID NO: 108);

[1505] Ac-R-R-Q-S-R-I-(Dox) (SEQ ID NO: 111);

[1506] Ac-L-R-R-Q-S-R-A-A-(Dox) (SEQ ID NO: 106);

[1507] Ac-L-R-R-Q-S-R-G-G-(Dox) (SEQ ID NO: 109);

[1508] Ac-L-R-R-Q-S-R-A-(Dox) (SEQ ID NO: 110);

[1509] Ac-L-R-R-Q-S-R-A-I-(Dox) (SEQ ID NO: 112);

[1510] Ac-L-R-R-Q-S-R-A-I-(Dox) (SEQ ID NO: 611);

[1511] Ac-L-R-R-Q-S-R-S-S-L-(Dox) (SEQ ID NO: 550);

[1512] Ac-L-R-R-Q-S-R-S-L-(Dox) (SEQ ID NO: 551);

[1513] Ac-S-G-R-S-L-(Dox) (SEQ ID NO: 362);

[1514] Ac-S-G-R-S-S-L-(Dox) (SEQ ID NO: 363);

[1515] Ac-S-G-R-S-S-S-L-(Dox) (SEQ ID NO: 364);

[1516] Ac-S-G-R-S-nL-(Dox) (SEQ ID NO: 365);

[1517] Ac-S-G-R-S-nV-(Dox) (SEQ ID NO: 366); isomer 1

[1518] Ac-S-G-R-S-nV-(Dox) (SEQ ID NO: 367); isomer 2

[1519] Ac-S-G-R-S-G(hex)-(Dox) (SEQ ID NO: 368);

[1520] Ac-S-G-R-S-Cha-(Dox) (SEQ ID NO: 369);

[1521] Ac-S-G-R-S-hCha-(Dox) (SEQ ID NO: 370);

[1522] Ac-S-A-R-S-L-(Dox) (SEQ ID NO: 371);

[1523] Ac-S-A-R-S-S-L-(Dox) (SEQ ID NO: 372);

[1524] Ac-S-S-R-S-nL-(Dox) (SEQ ID NO: 373);

[1525] Ac-T-G-R-S-Abu-(Dox) (SEQ ID NO: 374);

[1526] Ac-T-G-R-S-L-(Dox) (SEQ ID NO: 375);

[1527] Ac-T-G-R-S-nV-(Dox) (SEQ ID NO: 376);

[1528] Ac-T-G-R-S-nL-(Dox) (SEQ ID NO: 377);

[1529] Ac-T-G-R-S-G(hex)-(Dox) (SEQ ID NO: 378);

[1530] Ac-T-G-R-S-Cha-(Dox) (SEQ ID NO: 379);

[1531] Ac-T-G-R-S-hCha-(Dox) (SEQ ID NO: 380);

[1532] Ac-T-G-R-T-Abu-(Dox) (SEQ ID NO: 381);

[1533] Ac-T-G-R-hS-nL-(Dox) (SEQ ID NO: 382);

[1534] Ac-T-G-R-Abu-nL-(Dox) (SEQ ID NO: 383);

[1535] Ac-T-G-R-Abu-nV-(Dox) (SEQ ID NO: 384);

[1536] Ac-T-G-F(Gn)-S-nL-(Dox) (SEQ ID NO: 385);

[1537] Ac-T-G-F(Gn)-S-Cha-(Dox) (SEQ ID NO: 386);

[1538] Ac-T-G-F(Gn)-Abu-nV-(Dox) (SEQ ID NO: 387);

[1539] Ac-T-G-K(alloc)-S-nL-(Dox) (SEQ ID NO: 388);

[1540] Ac-T-G-K-S-nL-(Dox) (SEQ ID NO: 389);

[1541] Ac-T-G-hR-S-nL-(Dox) (SEQ ID NO: 390);

[1542] Ac-(hS)G-G-R-S-nL-(Dox) (SEQ ID NO: 391);

[1543] MeOCO-T-G-R-S-nL-(Dox) (SEQ ID NO: 392);

[1544] PhSO2-T-G-R-S-nL-(Dox) (SEQ ID NO: 393);

[1545] MeOEtCO-T-G-R-S-nL-(Dox) (SEQ ID NO: 394);

[1546] MeO(EtO)2Ac-T-G-R-S-nL-(Dox) (SEQ ID NO: 395);

[1547] 4-oxo-Pentanoyl-T-G-R-S-nL-(Dox) (SEQ ID NO: 396);

[1548] 3,4-MethyldioxyPhAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 397);

[1549] 2-PyridilAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 398);

[1550] PhOAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 399);

[1551] L-3-PhLactyl-T-G-R-S-nL-(Dox) (SEQ ID NO: 400);

[1552] MeOAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 401);

[1553] PhAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 402);

[1554] MeOEtOCO-T-G-R-S-nL-(Dox) (SEQ ID NO: 403);

[1555] MeOEtOAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 404);

[1556] HOOCButa-T-G-R-S-nL-(Dox) (SEQ ID NO: 405);

[1557] Z-T-G-R-S-nL-(Dox) (SEQ ID NO: 406);

[1558] EtOCO-T-G-R-S-nL-(Dox) (SEQ ID NO: 407);

[1559] βA-T-G-R-S-nL-(Dox) (SEQ ID NO: 408);

[1560] Pent-4-ynoyl-T-G-R-S-nL-(Dox) (SEQ ID NO: 409);

[1561] NapAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 410);

[1562] iBoc-T-G-R-S-nL-(Dox) (SEQ ID NO: 411);

[1563] HOAc-T-G-R-S-nL-(Dox) (SEQ ID NO: 412);

[1564] MeSucc-T-G-R-S-nL-(Dox) (SEQ ID NO: 413);

[1565] N,N-diMeGly-T-G-R-S-nL-(Dox) (SEQ ID NO: 414);

[1566] Succ-T-G-R-S-nL-(Dox) (SEQ ID NO: 415);

[1567] HCO-T-G-R-S-nL-(Dox) (SEQ ID NO: 416);

[1568] Ac-T-A-R-S-nL-(Dox) (SEQ ID NO: 417);

[1569] Ac-T-A-F(Gn)-S-nL-(Dox) (SEQ ID NO: 418);

[1570] Ac-T-A-R-Abu-nV-(Dox) (SEQ ID NO: 419);

[1571] Ac-T-A-R-S-Abu-(Dox) (SEQ ID NO: 420);

[1572] Ac-T-A-R-T-Abu-(Dox) (SEQ ID NO: 421);

[1573] Ac-T-S(O-Me)-R-S-nL-(Dox) (SEQ ID NO: 422);

[1574] Ac-T-hS-R-S-nL-(Dox) (SEQ ID NO: 423);

[1575] Ac-T-(1-Me)H-R-S-nL-(Dox) (SEQ ID NO: 424);

[1576] Ac-T-(3-Me)H-R-S-nL-(Dox) (SEQ ID NO: 425);

[1577] Ac-T-H-R-S-nL-(Dox) (SEQ ID NO: 426);

[1578] Ac-T-Sar-R-S-nL-(Dox) (SEQ ID NO: 427);

[1579] Ac-T-nV-R-S-nL-(Dox) (SEQ ID NO: 428);

[1580] Ac-T-nL-R-S-nL-(Dox) (SEQ ID NO: 429);

[1581] Ac-T-A-R-S-Cha-(Dox) (SEQ ID NO: 430);

[1582] Ac-T-Abu-R-S-nL-(Dox) (SEQ ID NO: 431);

[1583] Ac-4,4diMeThr-G-R-S-nL-(Dox) (SEQ ID NO: 432);

[1584] Ac-hS-G-R-S-nL-(Dox) (SEQ ID NO: 433);

[1585] Ac-hS-G-R-hS-Cha-(Dox) (SEQ ID NO: 434);

[1586] Ac-hS-G-R-S-Cha-(Dox) (SEQ ID NO: 435);

[1587] Ac-hS-G-R-T-Cha-(Dox) (SEQ ID NO: 436);

[1588] Ac-hS-A-R-S-Cha-(Dox) (SEQ ID NO: 437);

[1589] Ac-N-G-R-S-nL-(Dox) (SEQ ID NO: 438);

[1590] Ac-Y-G-R-S-S-L-(Dox) (SEQ ID NO: 439);

[1591] Ac-Y-G-R-S-Cha-(Dox) (SEQ ID NO: 440);

[1592] Ac-Q-G-R-S-S-nL-(Dox) (SEQ ID NO: 441);

[1593] Ac-Q-G-R-S-S-nV-(Dox) (SEQ ID NO: 442);

[1594] Ac-L-R-G-S-G-R-S-A-(Dox) (SEQ ID NO: 573);

[1595] Ac-L-R-G-S-G-R-S-L-(Dox) (SEQ ID NO: 342);

[1596] Ac-L-R-G-S-G-R-S-L-(Dox) (SEQ ID NO: 343);

[1597] Ac-L-R-G-S-G-R-S-S-nL-(Dox) (SEQ ID NO: 344);

[1598] Ac-L-R-G-S-G-R-S-S-Cha-(Dox) (SEQ ID NO: 345);

[1599] Ac-L-R-G-dS-A-R-S-A-(Dox) (SEQ ID NO: 574);

[1600] Ac-L-R-G-S-A-R-S-S-L-(Dox) (SEQ ID NO: 346);

[1601] Ac-L-R-G-S-A-R-S-L-(Dox) (SEQ ID NO: 347);

[1602] Ac-L-R-G-S-A-R-S-S-Cha-(Dox) (SEQ ID NO: 348);

[1603] Ac-L-R-G-S-A-R-S-S-nV-(Dox) (SEQ ID NO: 349);

[1604] Ac-L-R-G-S-A-R-S-S-nL-(Dox) (SEQ ID NO: 350);

[1605] Ac-V-I-V-S-G-R-A-L-(Dox) (SEQ ID NO: 351);

[1606] Ac-V-I-V-S-A-R-S-L-(Dox) (SEQ ID NO: 352);

[1607] Ac-V-I-V-S-G-R-S-S-L-(Dox) (SEQ ID NO: 353);

[1608] Ac-V-I-V-S-A-R-M-A-(Dox) (SEQ ID NO: 354);

[1609] Ac-V-I-V-S-A-R-nL-A-(Dox) (SEQ ID NO: 355);

[1610] Ac-V-I-V-S-A-R-S-nL-(Dox) (SEQ ID NO: 356);

[1611] Ac-V-I-V-S-A-R-S-Cha-(Dox) (SEQ ID NO: 357);

[1612] Ac-V-I-V-S-A-R-S-Cha-(Dox) (SEQ ID NO: 358);

[1613] Ac-V-I-V-S-A-R-S-S-Cha-(Dox) (SEQ ID NO: 359);

[1614] Ac-R-R-(Me)C-P-G-R-V-V-(Dox) (SEQ ID NO: 360);

[1615] Ac-R-R-nV-P-A-R-S-L-(Dox) (SEQ ID NO: 361);

[1616] Ac-R-G-dS-A-R-S-A-(Dox) (SEQ ID NO: 309);

[1617] Ac-R-G-S-G-R-S-A-(Dox) (SEQ ID NO: 310);

[1618] Ac-R-G-S-G-R-A-L-(Dox) (SEQ ID NO: 311);

[1619] Ac-R-G-S-G-R-S-L-(Dox) (SEQ ID NO: 312);

[1620] Ac-R-G-S-G-R--S-nL-(Dox) (SEQ ID NO: 313);

[1621] Ac-R-G-S-G-R-A-nL-(Dox) (SEQ ID NO: 314);

[1622] Ac-R-G-S-G-R-S-S-L-(Dox) (SEQ ID NO: 315);

[1623] Ac-R-G-S-G-R-S-Cha-(Dox) (SEQ ID NO: 316);

[1624] Ac-R-G-S-G-R-S-S-Cha-(Dox) (SEQ ID NO: 317);

[1625] Ac-R-G-S-A-R-S-Cha-(Dox) (SEQ ID NO: 318);

[1626] Ac-R-G-S-A-R-S-S-(Dox) (SEQ ID NO: 319);

[1627] Ac-R-G-S-A-R-S-nV-(Dox) (SEQ ID NO: 320);

[1628] Ac-R-G-S-A-R-S-S-nV-(Dox) (SEQ ID NO: 321);

[1629] Ac-R-G-S-A-R-S-L-(Dox) (SEQ ID NO: 322);

[1630] Ac-R-(Me)C-P-G-R-V-V-(Dox) (SEQ ID NO: 323);

[1631] Ac-R-(Me)C-P-G-R-V-V-(Dox) (SEQ ID NO: 324);

[1632] Ac-R-C(Me)-P-G-R-S-L-(Dox) (SEQ ID NO: 325);

[1633] Ac-R-L-P-G-R-S-L-(Dox) (SEQ ID NO: 326);

[1634] Ac-R-V-P-G-R-S-L-(Dox) (SEQ ID NO: 327);

[1635] Ac-R-V-P-G-R-S-L-(Dox) (SEQ ID NO: 328);

[1636] Ac-R-nL-P-G-R-S-L-(Dox) (SEQ ID NO: 329);

[1637] Ac-R-G(tBu)-P-A-R-S-L-(Dox) (SEQ ID NO: 330);

[1638] Ac-R-L-P-A-R-S-L-(Dox) (SEQ ID NO: 331);

[1639] Ac-R-V-P-A-R-S-L-(Dox) (SEQ ID NO: 332);

[1640] Ac-R-nL-P-A-R-S-L-(Dox) (SEQ ID NO: 333);

[1641] Ac-I-V-S-G-R-A-L-(Dox) (SEQ ID NO: 334);

[1642] Ac-I-V-S-G-R-S-S-L-(Dox) (SEQ ID NO: 335);

[1643] Ac-I-V-S-G-R-A-S-L-(Dox) (SEQ ID NO: 336);

[1644] Ac-I-V-S-A-R-M-A-(Dox) (SEQ ID NO: 337);

[1645] Ac-I-V-S-A-R-nL-A-(Dox) (SEQ ID NO: 338);

[1646] Ac-I-V-S-A-R-S-L-(Dox) (SEQ ID NO: 339);

[1647] Ac-I-V-S-A-R-S-nL-(Dox) (SEQ ID NO: 340);

[1648] Ac-I-V-S-A-R-S-S-L-(Dox) (SEQ ID NO: 341);

[1649] Ac-G-S-G-R-S-A-(Dox) (SEQ ID NO: 585);

[1650] Ac-G-S-G-R-S-L-(Dox) (SEQ ID NO: 277);

[1651] Ac-G-S-G-R-A-L-(Dox) (SEQ ID NO: 278);

[1652] Ac-G-S-G-R-S-S-L-(Dox) (SEQ ID NO: 279);

[1653] Ac-G-S-G-R-L-(Dox) (SEQ ID NO: 280);

[1654] Ac-G-S-G-(4-guan)Phg-S-L-NH2 (SEQ ID NO: 281);

[1655] Ac-G-S-G-R-S-S-Cha-(Dox) (SEQ ID NO: 282);

[1656] Ac-G-S-G-R-A-S-L-(Dox) (SEQ ID NO: 283);

[1657] Ac-G-S-G-R-S-nL-(Dox) (SEQ ID NO: 284);

[1658] Ac-G-T-G-R-S-nL-(Dox) (SEQ ID NO: 285);

[1659] Succ-bA-T-G-R-S-nL-(Dox) (SEQ ID NO: 286);

[1660] Ac-G-T-G-R-S-hCha-(Dox) (SEQ ID NO: 287);

[1661] Ac-G-hS-G-R-S-nL-(Dox) (SEQ ID NO: 288);

[1662] Ac-G-dS-A-R-S-A-(Dox) (SEQ ID NO: 289);

[1663] Ac-G-S-A-R-S-L-(Dox) (SEQ ID NO: 290);

[1664] Ac-G-S-A-R-S-S-Cha-(Dox) (SEQ ID NO: 291);

[1665] Ac-G-S-A-R-S-S-L-(Dox) (SEQ ID NO: 292);

[1666] Ac-G-S-A-R-A-S-L-(Dox) (SEQ ID NO: 293);

[1667] Ac-V-S-G-R-S-L-(Dox) (SEQ ID NO: 294);

[1668] Ac-V-S-G-R-A-L-(Dox) (SEQ ID NO: 295);

[1669] Ac-V-S-G-R-A-S-L-(Dox) (SEQ ID NO: 296);

[1670] Ac-V-S-G-R-S-S-L-(Dox) (SEQ ID NO: 297);

[1671] Ac-V-S-A-R-M-A-(Dox) (SEQ ID NO: 298);

[1672] Ac-V-S-A-R-nL-A-(Dox) (SEQ ID NO: 299);

[1673] Ac-V-S-A-R-S-nL-(Dox) (SEQ ID NO: 300);

[1674] Ac-V-S-A-R-S-L-(Dox) (SEQ ID NO: 301);

[1675] Ac-(Me)C-P-G-R-V-V-(Dox) (SEQ ID NO: 302);

[1676] Ac-(Me)C-P-G-R-V-V-(Dox) (SEQ ID NO: 303);

[1677] Ac-C(Me)-P-G-R-A-L-(Dox) (SEQ ID NO: 304);

[1678] Ac-C(Me)-P-G-R-S-L-(Dox) (SEQ ID NO: 305);

[1679] Ac-C(Me)-P-A-R-S-L-(Dox) (SEQ ID NO: 306);

[1680] Ac-C(Me)-P-A-R-A-S-L-(Dox) (SEQ ID NO: 307);

[1681] Ac-G(tBu)-P-G-R-S-L-(Dox) (SEQ ID NO: 308);

[1682] Ac-Q-S-R-A-A-(taxol) (SEQ ID NO: 552);

[1683] Ac-Q-S-R-S-A-(taxol) (SEQ ID NO: 553);

[1684] Ac-Q-S-R-S-G-(taxol) (SEQ ID NO: 554);

[1685] Ac-R-S-R-A-A-(taxol) (SEQ ID NO: 555);

[1686] Ac-R-Q-S-R-A-A-(taxol) (SEQ ID NO: 556);

[1687] Ac-R-Q-S-R-S-A-(taxol) (SEQ ID NO: 557);

[1688] Ac-R-Q-S-R-S-A-A-(taxol) (SEQ ID NO: 558);

[1689] Ac-R-G-S-G-R-S-A-(taxol) (SEQ ID NO: 559);

[1690] Ac-S-G-R-A-A-(taxol) (SEQ ID NO: 560);

[1691] Ac-S-G-R-S-A-(taxol) (SEQ ID NO: 561);

[1692] Ac-S-G-R-S-S-A-(taxol) (SEQ ID NO: 562);

[1693] Ac-S-G-R-A-S-A-(taxol) (SEQ ID NO: 563);

[1694] Ac-S-G-R-S-G-(taxol) (SEQ ID NO: 564);

[1695] Ac-S-G-R-S-S-G-(taxol) (SEQ ID NO: 565);

[1696] Ac-S-G-R-S-G-A-(taxol) (SEQ ID NO: 566);

[1697] Ac-S-G-R-S-G-G-(taxol) (SEQ ID NO:567);

[1698] Ac-G-T-G-R-S-G-G-(taxol) (SEQ ID NO: 568);

[1699] Ac-L-R-R-Q-S-R-A-A-(Dox) (SEQ ID NO: 597);

[1700] MeSO2-dA(Chx)-Abu-R-S-L-(Dox) (SEQ ID NO: 598);

[1701] Ac-R-A-R-S-L-(Dox) (SEQ ID NO: 599);

[1702] Ac-dA(Chx)-Abu-R-S-L-(Dox) (SEQ ID NO: 600);

[1703] Ac-dA(Chx)-Abu-R-S-S-L-(Dox) (SEQ ID NO: 601);

[1704] Ac-Q-G-R-S-S-L-(Dox) (SEQ ID NO: 602);

[1705] MeOCO-dhF-P(OH)-R-S-S-L-(Dox) (SEQ ID NO: 603);

[1706] MeOCO-Quat4-G-R-S-L-(Dox) (SEQ ID NO: 604);

[1707] As-dCha-P(OH)-R-S-S-L-(Dox) (SEQ ID NO: 605);

[1708] Ac-dCha-Abu-R-S-S-A-(taxol) (SEQ ID NO: 606);

[1709] MeOCO-Quat2-G-R-S-L-NH2 (SEQ ID NO: 607);

[1710] MeOCO-Quat3-G-R-S-L-NH2 (SEQ ID NO: 608); and

[1711] MeOCO-Quat-G-R-S-L-NH2 (SEQ ID NO: 609).

EXAMPLE 10 Pharmacokinetic Studies of Conjugates and Fraction of theDose Metabolized to Doxorubicin and Leucine-Doxorubicin in Naïve andTumor Bearing Mice.

[1712] Naïve or tumor bearing nude mice 8-12 weeks of age have been usedfor pharmacokinetic studies of the test conjugates. Tumor cells forimplantation have been prepared following one of three protocols.

[1713] Protocol A Tumor Cells Collected from Tissue Culture

[1714] Tumor cells are trypsinized and resuspended in the growth mediumand centrifuged for 6 min at 200×g. The cells are resuspended inserum-free medium and counted. The appropriate volume of the solutioncontaining the desired number of cells is then transferred to a conicalcentrifuge tube, centrifuged as before and resuspended in theappropriate volume of a cold 1:1 mixture of cells in phenol freemedium:matrigel. Each mouse is inoculated with 0.2-0.5 mL containingbetween 1×10⁶ and 1×10⁷ tumor cells subcutaneously or orthotopically.

[1715] Protocol B Tumor Cell Suspension Established tumors (200-1000mm³) are dissected from mice, weighed and rinsed in tumor cell growthmedium. The tumors are passed through a steel cell dissociation sieve.The cells are rinsed through the sieve with growth medium. The cells arecentrifuged for 6 min at 200×g and resuspended in the appropriate volumeof a cold 1:1 mixture of cells:matrigel. Each mouse is inoculated with0.2-0.5 mL of tumor cells subcutaneously or orthotopically.

[1716] Protocol C Tumor Fragments

[1717] Alternatively a tumor measuring approximately 800 mm³ isdissected out of a mouse, rinsed in tumor cell growth medium and cutinto 1-2 mm³ fragments. Each fragment is inoculated subcutaneously ororthotopically using a trocar needle.

[1718] Pharmacokinetic Study

[1719] Naïve or tumor bearing mice are individually weighed and assignedto groups. The mice are dosed with 1-100 umole/kg, including 30umole/kg, 25 umole/kg, or 21.5 umole/kg of the test conjugateintraperitoneally or intravenously. At a given time point between 5minutes and 24 hours after administration of the compound the mice aresacrificed. Blood is collected in a syringe containing proteaseinhibitors such as EDTA, AEBSF, Aprotinin, Leupeptin, Bestatin,Pepstanin A or E64 and transferred into a heparinized blood collectiontube. The plasma is prepared by centrifugation. The tumors are collectedand pulverized in liquid nitrogen. The resulting tumor powders arestored at −80° C. The tumor powders and plasma are extracted andanalyzed for the parent test conjugate and its products includingLeucine-doxorubicin (or norleucine-doxorubicin, etc.) and doxorubicin.

[1720] Looking at the delivery of the toxin to the tumor cells, and alsolooking at the parent conjugate and the levels of toxin (dox and nor-leudox) in the plasma.

[1721] Results

[1722] For example, test conjugate (21.5 umole/kg ofAc-Gly-Ser-Gly-Arg-Ser-nLeu-Dox (see Example 2)) was administered tonaive and tumor bearing (TB) mice intraperitoneally (IP) orintravenously (IV). One hour after administration plasma and tumortissue was collected from the mice. Concentrations of the test conjugateand its products are compared. The results show that the conjugate doesnot get into the tumor, the toxins (norleu dox and dox—μM concentrationsin the tumor at one hour following the single (both IP and IV)injection. There were lower levels of dox and nor-leu dox the plasmathan in the tumor.

[1723] Extraction, Chromatography LC/MS Conditions

[1724] Plasma: Plasma samples are prepared using acetonitrile proteinprecipitation. A standard curve was constructed from addition of 5 to 20μL volumes of a standard compound to 0.1 mL or 0.05 mL volumes of plasmaon ice. The standard curve ranges from 10 ng/mL-1 ug/mL or from 100ng/mL-4 ug/mL of the standard compound. Immediumtely after standardaddition, acetonitrile is added to precipitate the proteins. The studyplasma samples were prepared by thawing the frozen plasma samples onice. The aliquots were added directly to the acetonitrile. After sampleprecipitation, the sample is mixed using vortex mixing. The precipitatewas pelleted using centrifugation. The supernatent was dried usingvacuum centrifugation. The sample was reconstituted with 0.15 mL of 30%acetonitrile—70% (0.01 M ammonium acetate with 0.1% formic acid). 0.01mL of the sample was injected for LC-MS analysis. The HPLC conditionswere a linear gradient of 20% acetonitrile—80% (10 mM ammoniumacetate—0.1% formic acid) to 50% acetonitrile—50% (10 mM ammoniumacetate—0.1% formic acid) in 1 minute at 0.3 mL/min in a 30×2.1 mmZorbax SB C18 HPLC column. Detection was provided by a triple quad massspectrometer with electrospray ionization. Doxorubicin was monitoredusing the m/z transition 544.1-396.8. Leucine-doxorubicin was monitoredusing 657.2-242.8. An exemplary parent conjugate was monitored using1555.9-1555.9. Scanning LC-MS and fluorescence detection was used toidentify cleavage products other than doxorubicin or leucine-doxorubicin(or norleucine-doxorubicin, etc.) in the plasma.

[1725] Tumor: Immediately after excision from the mouse, the tumor foranalysis is weighed and placed into a mortar containing liquid nitrogen.With the mortar nested in a bed of dry ice, the tumor is ground into afine powder while additional liquid nitrogen is added as needed to avoidthawing. When a homogeneous tumor powder is achieved, the remainingliquid nitrogen is allowed to boil off. The tumor powder isquantitatively transferred to a 15 ml conical tube that has beenpre-chilled and is on dry ice. The sample is stored at −70° C. untilanalysis. The tumor powder is thawed on ice and vortex mixed with 0.01 Mammonium acetate in a 1 gram tumor/mL ammonium acetate solutionconcentration to form a slurry. An aliquot of 0.1 mL of the tumor slurryis precipitated with 0.5 mL acetonitrile. The supernatant is separatedfrom the precipitated solids and then evaporated using vacuumcentrifugation. Quantification of doxorubicin, leucine-doxorubicin (ornorleucine-docorubicin, etc.), is achieved by reference to a standardcurve constructed from spiking measured amounts of standard compounds(doxorubicin, leucine-doxorubicin, etc.) into control tumor slurry. Atypical standard curve ranges from 1 ng to 200 ng of compound peraliquot of tumor slurry. After the unknown samples and standards areprocessed and dried, the residue is reconstituted in 0.15 mL of 30%acetonitrile—70% (0.01 M ammonium acetate+0.1% formic acid). 10 μL ofsolution is injected onto a liquid chromatography—mass spectrometrysystem. The HPLC conditions were a linear gradient of 20%acetonitrile—80% (10 mM ammonium acetate—0.1% formic acid) to 50%acetonitrile—50% (10 mM ammonium acetate—0.1% formic acid) in 1 minuteat 0.3 mL/min in a 30×2.1 mm Zorbax SB C18 HPLC column. Detection wasprovided by a triple quad mass spectrometer with electrosprayionization. Doxorubicin was monitored using the m/z transition544.1-396.8. Leucine-doxorubicin was monitored using 657.2-242.8.

[1726] Since modifications will be apparent to those of skill in thisart, it is intended that this invention be limited only by the scope ofthe appended claims.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 611 <210> SEQ ID NO 1<211> LENGTH: 3147 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (23)...(2589) <223> OTHERINFORMATION: Nucleotide sequence encoding MTSP1 <300> PUBLICATIONINFORMATION: <301> AUTHORS: O′Brien, T.J. and Tanimoto, H. <308>DATABASE ACCESSION NUMBER: GenBank AR081724 <309> DATABASE ENTRY DATE:2000-08-31 <310> PATENT DOCUMENT NUMBER: US Pat 5972616 <311> PATENTFILING DATE: 1998-02-20 <312> PUBLICATION DATE: 1999-10-26 <400>SEQUENCE: 1 tcaagagcgg cctcggggta cc atg ggg agc gat cgg gcc cgc aag ggcgga 52 Met Gly Ser Asp Arg Ala Arg Lys Gly Gly 1 5 10 ggg ggc ccg aaggac ttc ggc gcg gga ctc aag tac aac tcc cgg cac 100 Gly Gly Pro Lys AspPhe Gly Ala Gly Leu Lys Tyr Asn Ser Arg His 15 20 25 gag aaa gtg aat ggcttg gag gaa ggc gtg gag ttc ctg cca gtc aac 148 Glu Lys Val Asn Gly LeuGlu Glu Gly Val Glu Phe Leu Pro Val Asn 30 35 40 aac gtc aag aag gtg gaaaag cat ggc ccg ggg cgc tgg gtg gtg ctg 196 Asn Val Lys Lys Val Glu LysHis Gly Pro Gly Arg Trp Val Val Leu 45 50 55 gca gcc gtg ctg atc ggc ctcctc ttg gtc ttg ctg ggg atc ggc ttc 244 Ala Ala Val Leu Ile Gly Leu LeuLeu Val Leu Leu Gly Ile Gly Phe 60 65 70 ctg gtg tgg cat ttg cag tac cgggac gtg cgt gtc cag aag gtc ttc 292 Leu Val Trp His Leu Gln Tyr Arg AspVal Arg Val Gln Lys Val Phe 75 80 85 90 aat ggc tac atg agg atc aca aatgag aat ttt gtg gat gcc tac gag 340 Asn Gly Tyr Met Arg Ile Thr Asn GluAsn Phe Val Asp Ala Tyr Glu 95 100 105 aac tcc aac tcc act gag ttt gtaagc ctg gcc agc aag gtg aag gac 388 Asn Ser Asn Ser Thr Glu Phe Val SerLeu Ala Ser Lys Val Lys Asp 110 115 120 gcg ctg aag ctg ctg tac agc ggagtc cca ttc ctg ggc ccc tac cac 436 Ala Leu Lys Leu Leu Tyr Ser Gly ValPro Phe Leu Gly Pro Tyr His 125 130 135 aag gag tcg gct gtg acg gcc ttcagc gag ggc agc gtc atc gcc tac 484 Lys Glu Ser Ala Val Thr Ala Phe SerGlu Gly Ser Val Ile Ala Tyr 140 145 150 tac tgg tct gag ttc agc atc ccgcag cac ctg gtg gag gag gcc gag 532 Tyr Trp Ser Glu Phe Ser Ile Pro GlnHis Leu Val Glu Glu Ala Glu 155 160 165 170 cgc gtc atg gcc gag gag cgcgta gtc atg ctg ccc ccg cgg gcg cgc 580 Arg Val Met Ala Glu Glu Arg ValVal Met Leu Pro Pro Arg Ala Arg 175 180 185 tcc ctg aag tcc ttt gtg gtcacc tca gtg gtg gct ttc ccc acg gac 628 Ser Leu Lys Ser Phe Val Val ThrSer Val Val Ala Phe Pro Thr Asp 190 195 200 tcc aaa aca gta cag agg acccag gac aac agc tgc agc ttt ggc ctg 676 Ser Lys Thr Val Gln Arg Thr GlnAsp Asn Ser Cys Ser Phe Gly Leu 205 210 215 cac gcc cgc ggt gtg gag ctgatg cgc ttc acc acg ccc ggc ttc cct 724 His Ala Arg Gly Val Glu Leu MetArg Phe Thr Thr Pro Gly Phe Pro 220 225 230 gac agc ccc tac ccc gct catgcc cgc tgc cag tgg gcc ctg cgg ggg 772 Asp Ser Pro Tyr Pro Ala His AlaArg Cys Gln Trp Ala Leu Arg Gly 235 240 245 250 gac gcc gac tca gtg ctgagc ctc acc ttc cgc agc ttt gac ctt gcg 820 Asp Ala Asp Ser Val Leu SerLeu Thr Phe Arg Ser Phe Asp Leu Ala 255 260 265 tcc tgc gac gag cgc ggcagc gac ctg gtg acg gtg tac aac acc ctg 868 Ser Cys Asp Glu Arg Gly SerAsp Leu Val Thr Val Tyr Asn Thr Leu 270 275 280 agc ccc atg gag ccc cacgcc ctg gtg cag ttg tgt ggc acc tac cct 916 Ser Pro Met Glu Pro His AlaLeu Val Gln Leu Cys Gly Thr Tyr Pro 285 290 295 ccc tcc tac aac ctg accttc cac tcc tcc cag aac gtc ctg ctc atc 964 Pro Ser Tyr Asn Leu Thr PheHis Ser Ser Gln Asn Val Leu Leu Ile 300 305 310 aca ctg ata acc aac actgag cgg cgg cat ccc ggc ttt gag gcc acc 1012 Thr Leu Ile Thr Asn Thr GluArg Arg His Pro Gly Phe Glu Ala Thr 315 320 325 330 ttc ttc cag ctg cctagg atg agc agc tgt gga ggc cgc tta cgt aaa 1060 Phe Phe Gln Leu Pro ArgMet Ser Ser Cys Gly Gly Arg Leu Arg Lys 335 340 345 gcc cag ggg aca ttcaac agc ccc tac tac cca ggc cac tac cca ccc 1108 Ala Gln Gly Thr Phe AsnSer Pro Tyr Tyr Pro Gly His Tyr Pro Pro 350 355 360 aac att gac tgc acatgg aac att gag gtg ccc aac aac cag cat gtg 1156 Asn Ile Asp Cys Thr TrpAsn Ile Glu Val Pro Asn Asn Gln His Val 365 370 375 aag gtg agc ttc aaattc ttc tac ctg ctg gag ccc ggc gtg cct gcg 1204 Lys Val Ser Phe Lys PhePhe Tyr Leu Leu Glu Pro Gly Val Pro Ala 380 385 390 ggc acc tgc ccc aaggac tac gtg gag atc aat ggg gag aaa tac tgc 1252 Gly Thr Cys Pro Lys AspTyr Val Glu Ile Asn Gly Glu Lys Tyr Cys 395 400 405 410 gga gag agg tcccag ttc gtc gtc acc agc aac agc aac aag atc aca 1300 Gly Glu Arg Ser GlnPhe Val Val Thr Ser Asn Ser Asn Lys Ile Thr 415 420 425 gtt cgc ttc cactca gat cag tcc tac acc gac acc ggc ttc tta gct 1348 Val Arg Phe His SerAsp Gln Ser Tyr Thr Asp Thr Gly Phe Leu Ala 430 435 440 gaa tac ctc tcctac gac tcc agt gac cca tgc ccg ggg cag ttc acg 1396 Glu Tyr Leu Ser TyrAsp Ser Ser Asp Pro Cys Pro Gly Gln Phe Thr 445 450 455 tgc cgc acg gggcgg tgt atc cgg aag gag ctg cgc tgt gat ggc tgg 1444 Cys Arg Thr Gly ArgCys Ile Arg Lys Glu Leu Arg Cys Asp Gly Trp 460 465 470 gcc gac tgc accgac cac agc gat gag ctc aac tgc agt tgc gac gcc 1492 Ala Asp Cys Thr AspHis Ser Asp Glu Leu Asn Cys Ser Cys Asp Ala 475 480 485 490 ggc cac cagttc acg tgc aag aac aag ttc tgc aag ccc ctc ttc tgg 1540 Gly His Gln PheThr Cys Lys Asn Lys Phe Cys Lys Pro Leu Phe Trp 495 500 505 gtc tgc gacagt gtg aac gac tgc gga gac aac agc gac gag cag ggg 1588 Val Cys Asp SerVal Asn Asp Cys Gly Asp Asn Ser Asp Glu Gln Gly 510 515 520 tgc agt tgtccg gcc cag acc ttc agg tgt tcc aat ggg aag tgc ctc 1636 Cys Ser Cys ProAla Gln Thr Phe Arg Cys Ser Asn Gly Lys Cys Leu 525 530 535 tcg aaa agccag cag tgc aat ggg aag gac gac tgt ggg gac ggg tcc 1684 Ser Lys Ser GlnGln Cys Asn Gly Lys Asp Asp Cys Gly Asp Gly Ser 540 545 550 gac gag gcctcc tgc ccc aag gtg aac gtc gtc act tgt acc aaa cac 1732 Asp Glu Ala SerCys Pro Lys Val Asn Val Val Thr Cys Thr Lys His 555 560 565 570 acc taccgc tgc ctc aat ggg ctc tgc ttg agc aag ggc aac cct gag 1780 Thr Tyr ArgCys Leu Asn Gly Leu Cys Leu Ser Lys Gly Asn Pro Glu 575 580 585 tgt gacggg aag gag gac tgt agc gac ggc tca gat gag aag gac tgc 1828 Cys Asp GlyLys Glu Asp Cys Ser Asp Gly Ser Asp Glu Lys Asp Cys 590 595 600 gac tgtggg ctg cgg tca ttc acg aga cag gct cgt gtt gtt ggg ggc 1876 Asp Cys GlyLeu Arg Ser Phe Thr Arg Gln Ala Arg Val Val Gly Gly 605 610 615 acg gatgcg gat gag ggc gag tgg ccc tgg cag gta agc ctg cat gct 1924 Thr Asp AlaAsp Glu Gly Glu Trp Pro Trp Gln Val Ser Leu His Ala 620 625 630 ctg ggccag ggc cac atc tgc ggt gct tcc ctc atc tct ccc aac tgg 1972 Leu Gly GlnGly His Ile Cys Gly Ala Ser Leu Ile Ser Pro Asn Trp 635 640 645 650 ctggtc tct gcc gca cac tgc tac atc gat gac aga gga ttc agg tac 2020 Leu ValSer Ala Ala His Cys Tyr Ile Asp Asp Arg Gly Phe Arg Tyr 655 660 665 tcagac ccc acg cag tgg acg gcc ttc ctg ggc ttg cac gac cag agc 2068 Ser AspPro Thr Gln Trp Thr Ala Phe Leu Gly Leu His Asp Gln Ser 670 675 680 cagcgc agc gcc cct ggg gtg cag gag cgc agg ctc aag cgc atc atc 2116 Gln ArgSer Ala Pro Gly Val Gln Glu Arg Arg Leu Lys Arg Ile Ile 685 690 695 tcccac ccc ttc ttc aat gac ttc acc ttc gac tat gac atc gcg ctg 2164 Ser HisPro Phe Phe Asn Asp Phe Thr Phe Asp Tyr Asp Ile Ala Leu 700 705 710 ctggag ctg gag aaa ccg gca gag tac agc tcc atg gtg cgg ccc atc 2212 Leu GluLeu Glu Lys Pro Ala Glu Tyr Ser Ser Met Val Arg Pro Ile 715 720 725 730tgc ctg ccg gac gcc tcc cat gtc ttc cct gcc ggc aag gcc atc tgg 2260 CysLeu Pro Asp Ala Ser His Val Phe Pro Ala Gly Lys Ala Ile Trp 735 740 745gtc acg ggc tgg gga cac acc cag tat gga ggc act ggc gcg ctg atc 2308 ValThr Gly Trp Gly His Thr Gln Tyr Gly Gly Thr Gly Ala Leu Ile 750 755 760ctg caa aag ggt gag atc cgc gtc atc aac cag acc acc tgc gag aac 2356 LeuGln Lys Gly Glu Ile Arg Val Ile Asn Gln Thr Thr Cys Glu Asn 765 770 775ctc ctg ccg cag cag atc acg ccg cgc atg atg tgc gtg ggc ttc ctc 2404 LeuLeu Pro Gln Gln Ile Thr Pro Arg Met Met Cys Val Gly Phe Leu 780 785 790agc ggc ggc gtg gac tcc tgc cag ggt gat tcc ggg gga ccc ctg tcc 2452 SerGly Gly Val Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Ser 795 800 805810 agc gtg gag gcg gat ggg cgg atc ttc cag gcc ggt gtg gtg agc tgg 2500Ser Val Glu Ala Asp Gly Arg Ile Phe Gln Ala Gly Val Val Ser Trp 815 820825 gga gac ggc tgc gct cag agg aac aag cca ggc gtg tac aca agg ctc 2548Gly Asp Gly Cys Ala Gln Arg Asn Lys Pro Gly Val Tyr Thr Arg Leu 830 835840 cct ctg ttt cgg gac tgg atc aaa gag aac act ggg gta ta ggggccgggg2599 Pro Leu Phe Arg Asp Trp Ile Lys Glu Asn Thr Gly Val 845 850 855ccacccaaat gtgtacacct gcggggccac ccatcgtcca ccccagtgtg cacgcctgca 2659ggctggagac tggaccgctg actgcaccag cgcccccaga acatacactg tgaactcaat 2719ctccagggct ccaaatctgc ctagaaaacc tctcgcttcc tcagcctcca aagtggagct 2779gggaggtaga aggggaggac actggtggtt ctactgaccc aactgggggc aaaggtttga 2839agacacagcc tcccccgcca gccccaagct gggccgaggc gcgtttgtgt atatctgcct 2899cccctgtctg taaggagcag cgggaacgga gcttcggagc ctcctcagtg aaggtggtgg 2959ggctgccgga tctgggctgt ggggcccttg ggccacgctc ttgaggaagc ccaggctcgg 3019aggaccctgg aaaacagacg ggtctgagac tgaaattgtt ttaccagctc ccagggtgga 3079cttcagtgtg tgtatttgtg taaatgggta aaacaattta tttcttttta aaaaaaaaaa 3139aaaaaaaa 3147 <210> SEQ ID NO 2 <211> LENGTH: 855 <212> TYPE: PRT <213>ORGANISM: Homo Sapien <400> SEQUENCE: 2 Met Gly Ser Asp Arg Ala Arg LysGly Gly Gly Gly Pro Lys Asp Phe 1 5 10 15 Gly Ala Gly Leu Lys Tyr AsnSer Arg His Glu Lys Val Asn Gly Leu 20 25 30 Glu Glu Gly Val Glu Phe LeuPro Val Asn Asn Val Lys Lys Val Glu 35 40 45 Lys His Gly Pro Gly Arg TrpVal Val Leu Ala Ala Val Leu Ile Gly 50 55 60 Leu Leu Leu Val Leu Leu GlyIle Gly Phe Leu Val Trp His Leu Gln 65 70 75 80 Tyr Arg Asp Val Arg ValGln Lys Val Phe Asn Gly Tyr Met Arg Ile 85 90 95 Thr Asn Glu Asn Phe ValAsp Ala Tyr Glu Asn Ser Asn Ser Thr Glu 100 105 110 Phe Val Ser Leu AlaSer Lys Val Lys Asp Ala Leu Lys Leu Leu Tyr 115 120 125 Ser Gly Val ProPhe Leu Gly Pro Tyr His Lys Glu Ser Ala Val Thr 130 135 140 Ala Phe SerGlu Gly Ser Val Ile Ala Tyr Tyr Trp Ser Glu Phe Ser 145 150 155 160 IlePro Gln His Leu Val Glu Glu Ala Glu Arg Val Met Ala Glu Glu 165 170 175Arg Val Val Met Leu Pro Pro Arg Ala Arg Ser Leu Lys Ser Phe Val 180 185190 Val Thr Ser Val Val Ala Phe Pro Thr Asp Ser Lys Thr Val Gln Arg 195200 205 Thr Gln Asp Asn Ser Cys Ser Phe Gly Leu His Ala Arg Gly Val Glu210 215 220 Leu Met Arg Phe Thr Thr Pro Gly Phe Pro Asp Ser Pro Tyr ProAla 225 230 235 240 His Ala Arg Cys Gln Trp Ala Leu Arg Gly Asp Ala AspSer Val Leu 245 250 255 Ser Leu Thr Phe Arg Ser Phe Asp Leu Ala Ser CysAsp Glu Arg Gly 260 265 270 Ser Asp Leu Val Thr Val Tyr Asn Thr Leu SerPro Met Glu Pro His 275 280 285 Ala Leu Val Gln Leu Cys Gly Thr Tyr ProPro Ser Tyr Asn Leu Thr 290 295 300 Phe His Ser Ser Gln Asn Val Leu LeuIle Thr Leu Ile Thr Asn Thr 305 310 315 320 Glu Arg Arg His Pro Gly PheGlu Ala Thr Phe Phe Gln Leu Pro Arg 325 330 335 Met Ser Ser Cys Gly GlyArg Leu Arg Lys Ala Gln Gly Thr Phe Asn 340 345 350 Ser Pro Tyr Tyr ProGly His Tyr Pro Pro Asn Ile Asp Cys Thr Trp 355 360 365 Asn Ile Glu ValPro Asn Asn Gln His Val Lys Val Ser Phe Lys Phe 370 375 380 Phe Tyr LeuLeu Glu Pro Gly Val Pro Ala Gly Thr Cys Pro Lys Asp 385 390 395 400 TyrVal Glu Ile Asn Gly Glu Lys Tyr Cys Gly Glu Arg Ser Gln Phe 405 410 415Val Val Thr Ser Asn Ser Asn Lys Ile Thr Val Arg Phe His Ser Asp 420 425430 Gln Ser Tyr Thr Asp Thr Gly Phe Leu Ala Glu Tyr Leu Ser Tyr Asp 435440 445 Ser Ser Asp Pro Cys Pro Gly Gln Phe Thr Cys Arg Thr Gly Arg Cys450 455 460 Ile Arg Lys Glu Leu Arg Cys Asp Gly Trp Ala Asp Cys Thr AspHis 465 470 475 480 Ser Asp Glu Leu Asn Cys Ser Cys Asp Ala Gly His GlnPhe Thr Cys 485 490 495 Lys Asn Lys Phe Cys Lys Pro Leu Phe Trp Val CysAsp Ser Val Asn 500 505 510 Asp Cys Gly Asp Asn Ser Asp Glu Gln Gly CysSer Cys Pro Ala Gln 515 520 525 Thr Phe Arg Cys Ser Asn Gly Lys Cys LeuSer Lys Ser Gln Gln Cys 530 535 540 Asn Gly Lys Asp Asp Cys Gly Asp GlySer Asp Glu Ala Ser Cys Pro 545 550 555 560 Lys Val Asn Val Val Thr CysThr Lys His Thr Tyr Arg Cys Leu Asn 565 570 575 Gly Leu Cys Leu Ser LysGly Asn Pro Glu Cys Asp Gly Lys Glu Asp 580 585 590 Cys Ser Asp Gly SerAsp Glu Lys Asp Cys Asp Cys Gly Leu Arg Ser 595 600 605 Phe Thr Arg GlnAla Arg Val Val Gly Gly Thr Asp Ala Asp Glu Gly 610 615 620 Glu Trp ProTrp Gln Val Ser Leu His Ala Leu Gly Gln Gly His Ile 625 630 635 640 CysGly Ala Ser Leu Ile Ser Pro Asn Trp Leu Val Ser Ala Ala His 645 650 655Cys Tyr Ile Asp Asp Arg Gly Phe Arg Tyr Ser Asp Pro Thr Gln Trp 660 665670 Thr Ala Phe Leu Gly Leu His Asp Gln Ser Gln Arg Ser Ala Pro Gly 675680 685 Val Gln Glu Arg Arg Leu Lys Arg Ile Ile Ser His Pro Phe Phe Asn690 695 700 Asp Phe Thr Phe Asp Tyr Asp Ile Ala Leu Leu Glu Leu Glu LysPro 705 710 715 720 Ala Glu Tyr Ser Ser Met Val Arg Pro Ile Cys Leu ProAsp Ala Ser 725 730 735 His Val Phe Pro Ala Gly Lys Ala Ile Trp Val ThrGly Trp Gly His 740 745 750 Thr Gln Tyr Gly Gly Thr Gly Ala Leu Ile LeuGln Lys Gly Glu Ile 755 760 765 Arg Val Ile Asn Gln Thr Thr Cys Glu AsnLeu Leu Pro Gln Gln Ile 770 775 780 Thr Pro Arg Met Met Cys Val Gly PheLeu Ser Gly Gly Val Asp Ser 785 790 795 800 Cys Gln Gly Asp Ser Gly GlyPro Leu Ser Ser Val Glu Ala Asp Gly 805 810 815 Arg Ile Phe Gln Ala GlyVal Val Ser Trp Gly Asp Gly Cys Ala Gln 820 825 830 Arg Asn Lys Pro GlyVal Tyr Thr Arg Leu Pro Leu Phe Arg Asp Trp 835 840 845 Ile Lys Glu AsnThr Gly Val 850 855 <210> SEQ ID NO 3 <211> LENGTH: 2137 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (261)...(1574) <223> OTHER INFORMATION: Nucleic acid encodinga transmembrane serine protease (MTSP3) protein <400> SEQUENCE: 3ccatcctaat acgactcact atagggctcg agcggccgcc cgggcaggtc agagagaggc 60agcagcttgc tcagcggaca aggatgctgg gcgtgaggga ccaaggcctg ccctgcactc 120gggcctcctc cagccagtgc tgaccaggga cttctgacct gctggccagc caggacctgt 180gtggggaggc cctcctgctg ccttggggtg acaatctcag ctccaggcta cagggagacc 240gggaggatca cagagccagc atg tta cag gat cct gac agt gat caa cct ctg 293Met Leu Gln Asp Pro Asp Ser Asp Gln Pro Leu 1 5 10 aac agc ctc gat gtcaaa ccc ctg cgc aaa ccc cgt atc ccc atg gag 341 Asn Ser Leu Asp Val LysPro Leu Arg Lys Pro Arg Ile Pro Met Glu 15 20 25 acc ttc aga aag gtg gggatc ccc atc atc ata gca cta ctg agc ctg 389 Thr Phe Arg Lys Val Gly IlePro Ile Ile Ile Ala Leu Leu Ser Leu 30 35 40 gcg agt atc atc att gtg gttgtc ctc atc aag gtg att ctg gat aaa 437 Ala Ser Ile Ile Ile Val Val ValLeu Ile Lys Val Ile Leu Asp Lys 45 50 55 tac tac ttc ctc tgc ggg cag cctctc cac ttc atc ccg agg aag cag 485 Tyr Tyr Phe Leu Cys Gly Gln Pro LeuHis Phe Ile Pro Arg Lys Gln 60 65 70 75 ctg tgt gac gga gag ctg gac tgtccc ttg ggg gag gac gag gag cac 533 Leu Cys Asp Gly Glu Leu Asp Cys ProLeu Gly Glu Asp Glu Glu His 80 85 90 tgt gtc aag agc ttc ccc gaa ggg cctgca gtg gca gtc cgc ctc tcc 581 Cys Val Lys Ser Phe Pro Glu Gly Pro AlaVal Ala Val Arg Leu Ser 95 100 105 aag gac cga tcc aca ctg cag gtg ctggac tcg gcc aca ggg aac tgg 629 Lys Asp Arg Ser Thr Leu Gln Val Leu AspSer Ala Thr Gly Asn Trp 110 115 120 ttc tct gcc tgt ttc gac aac ttc acagaa gct ctc gct gag aca gcc 677 Phe Ser Ala Cys Phe Asp Asn Phe Thr GluAla Leu Ala Glu Thr Ala 125 130 135 tgt agg cag atg ggc tac agc agc aaaccc acc ttc aga gct gtg gag 725 Cys Arg Gln Met Gly Tyr Ser Ser Lys ProThr Phe Arg Ala Val Glu 140 145 150 155 att ggc cca gac cag gat ctg gatgtt gtt gaa atc aca gaa aac agc 773 Ile Gly Pro Asp Gln Asp Leu Asp ValVal Glu Ile Thr Glu Asn Ser 160 165 170 cag gag ctt cgc atg cgg aac tcaagt ggg ccc tgt ctc tca ggc tcc 821 Gln Glu Leu Arg Met Arg Asn Ser SerGly Pro Cys Leu Ser Gly Ser 175 180 185 ctg gtc tcc ctg cac tgt ctt gcctgt ggg aag agc ctg aag acc ccc 869 Leu Val Ser Leu His Cys Leu Ala CysGly Lys Ser Leu Lys Thr Pro 190 195 200 cgt gtg gtg ggt ggg gag gag gcctct gtg gat tct tgg cct tgg cag 917 Arg Val Val Gly Gly Glu Glu Ala SerVal Asp Ser Trp Pro Trp Gln 205 210 215 gtc agc atc cag tac gac ata cagcac gtc tgt gga ggg agc atc ctg 965 Val Ser Ile Gln Tyr Asp Ile Gln HisVal Cys Gly Gly Ser Ile Leu 220 225 230 235 gac ccc cac tgg gtc ctc acggca gcc cac tgc ttc agg aaa cat acc 1013 Asp Pro His Trp Val Leu Thr AlaAla His Cys Phe Arg Lys His Thr 240 245 250 gat gtg ttc aac tgg aag gtgcgg gca ggc tca gac aaa ctg ggc agc 1061 Asp Val Phe Asn Trp Lys Val ArgAla Gly Ser Asp Lys Leu Gly Ser 255 260 265 ttc cca tcc ctg gct gtg gccaag atc atc atc att gaa ttc aac ccc 1109 Phe Pro Ser Leu Ala Val Ala LysIle Ile Ile Ile Glu Phe Asn Pro 270 275 280 atg tac ccc aaa gac aat gacatc gcc ctc atg aag ctg cag ttc cca 1157 Met Tyr Pro Lys Asp Asn Asp IleAla Leu Met Lys Leu Gln Phe Pro 285 290 295 ctc act ttc tca ggc aca gtcagg ctc atc tgt ctg ccc ttc ttt gat 1205 Leu Thr Phe Ser Gly Thr Val ArgLeu Ile Cys Leu Pro Phe Phe Asp 300 305 310 315 gag gag ctc act cca gccacc cca ctc tgg atc att gga tgg ggc ttt 1253 Glu Glu Leu Thr Pro Ala ThrPro Leu Trp Ile Ile Gly Trp Gly Phe 320 325 330 acg aag cag aat gga gggaag atg tct gac ata ctg ctg cag gcg tca 1301 Thr Lys Gln Asn Gly Gly LysMet Ser Asp Ile Leu Leu Gln Ala Ser 335 340 345 gtc cag gtc att gac agcaca cgg tgc aat gca gac gat gcg tac cag 1349 Val Gln Val Ile Asp Ser ThrArg Cys Asn Ala Asp Asp Ala Tyr Gln 350 355 360 ggg gaa gtc acc gag aagatg atg tgt gca ggc atc ccg gaa ggg ggt 1397 Gly Glu Val Thr Glu Lys MetMet Cys Ala Gly Ile Pro Glu Gly Gly 365 370 375 gtg gac acc tgc cag ggtgac agt ggt ggg ccc ctg atg tac caa tct 1445 Val Asp Thr Cys Gln Gly AspSer Gly Gly Pro Leu Met Tyr Gln Ser 380 385 390 395 gac cag tgg cat gtggtg ggc atc gtt agc tgg ggc tat ggc tgc ggg 1493 Asp Gln Trp His Val ValGly Ile Val Ser Trp Gly Tyr Gly Cys Gly 400 405 410 ggc ccg agc acc ccagga gta tac acc aag gtc tca gcc tat ctc aac 1541 Gly Pro Ser Thr Pro GlyVal Tyr Thr Lys Val Ser Ala Tyr Leu Asn 415 420 425 tgg atc tac aat gtctgg aag gct gag ctg taa tgctgctgcc cctttgcagt 1594 Trp Ile Tyr Asn ValTrp Lys Ala Glu Leu * 430 435 gctgggagcc gcttccttcc tgccctgcccacctggggat cccccaaagt cagacacaga 1654 gcaagagtcc ccttgggtac acccctctgcccacagcctc agcatttctt ggagcagcaa 1714 agggcctcaa ttcctgtaag agaccctcgcagcccagagg cgcccagagg aagtcagcag 1774 ccctagctcg gccacacttg gtgctcccagcatcccaggg agagacacag cccactgaac 1834 aaggtctcag gggtattgct aagccaagaaggaactttcc cacactactg aatggaagca 1894 ggctgtcttg taaaagccca gatcactgtgggctggagag gagaaggaaa gggtctgcgc 1954 cagccctgtc cgtcttcacc catccccaagcctactagag caagaaacca gttgtaatat 2014 aaaatgcact gccctactgt tggtatgactaccgttacct actgttgtca ttgttattac 2074 agctatggcc actattatta aagagctgtgtaacaaaaaa aaaaaaaaaa aaaaaaaaaa 2134 aaa 2137 <210> SEQ ID NO 4 <211>LENGTH: 437 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE:4 Met Leu Gln Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp Val 1 5 1015 Lys Pro Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg Lys Val 20 2530 Gly Ile Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser Ile Ile Ile 35 4045 Val Val Val Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys 50 5560 Gly Gln Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu 65 7075 80 Leu Asp Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe 8590 95 Pro Glu Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr100 105 110 Leu Gln Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala CysPhe 115 120 125 Asp Asn Phe Thr Glu Ala Leu Ala Glu Thr Ala Cys Arg GlnMet Gly 130 135 140 Tyr Ser Ser Lys Pro Thr Phe Arg Ala Val Glu Ile GlyPro Asp Gln 145 150 155 160 Asp Leu Asp Val Val Glu Ile Thr Glu Asn SerGln Glu Leu Arg Met 165 170 175 Arg Asn Ser Ser Gly Pro Cys Leu Ser GlySer Leu Val Ser Leu His 180 185 190 Cys Leu Ala Cys Gly Lys Ser Leu LysThr Pro Arg Val Val Gly Gly 195 200 205 Glu Glu Ala Ser Val Asp Ser TrpPro Trp Gln Val Ser Ile Gln Tyr 210 215 220 Asp Ile Gln His Val Cys GlyGly Ser Ile Leu Asp Pro His Trp Val 225 230 235 240 Leu Thr Ala Ala HisCys Phe Arg Lys His Thr Asp Val Phe Asn Trp 245 250 255 Lys Val Arg AlaGly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala 260 265 270 Val Ala LysIle Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp 275 280 285 Asn AspIle Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly 290 295 300 ThrVal Arg Leu Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro 305 310 315320 Ala Thr Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn Gly 325330 335 Gly Lys Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val Ile Asp340 345 350 Ser Thr Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu Val ThrGlu 355 360 365 Lys Met Met Cys Ala Gly Ile Pro Glu Gly Gly Val Asp ThrCys Gln 370 375 380 Gly Asp Ser Gly Gly Pro Leu Met Tyr Gln Ser Asp GlnTrp His Val 385 390 395 400 Val Gly Ile Val Ser Trp Gly Tyr Gly Cys GlyGly Pro Ser Thr Pro 405 410 415 Gly Val Tyr Thr Lys Val Ser Ala Tyr LeuAsn Trp Ile Tyr Asn Val 420 425 430 Trp Lys Ala Glu Leu 435 <210> SEQ IDNO 5 <211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (1)...(708) <223> OTHERINFORMATION: Nucleic acid encoding an MTSP4 protease domain <400>SEQUENCE: 5 att gtt ggt gga gct gtg tcc tcc gag ggt gag tgg cca tgg caggcc 48 Ile Val Gly Gly Ala Val Ser Ser Glu Gly Glu Trp Pro Trp Gln Ala 15 10 15 agc ctc cag gtt cgg ggt cga cac atc tgt ggg ggg gcc ctc atc gct96 Ser Leu Gln Val Arg Gly Arg His Ile Cys Gly Gly Ala Leu Ile Ala 20 2530 gac cgc tgg gtg ata aca gct gcc cac tgc ttc cag gag gac agc atg 144Asp Arg Trp Val Ile Thr Ala Ala His Cys Phe Gln Glu Asp Ser Met 35 40 45gcc tcc acg gtg ctg tgg acc gtg ttc ctg ggc aag gtg tgg cag aac 192 AlaSer Thr Val Leu Trp Thr Val Phe Leu Gly Lys Val Trp Gln Asn 50 55 60 tcgcgc tgg cct gga gag gtg tcc ttc aag gtg agc cgc ctg ctc ctg 240 Ser ArgTrp Pro Gly Glu Val Ser Phe Lys Val Ser Arg Leu Leu Leu 65 70 75 80 cacccg tac cac gaa gag gac agc cat gac tac gac gtg gcg ctg ctg 288 His ProTyr His Glu Glu Asp Ser His Asp Tyr Asp Val Ala Leu Leu 85 90 95 cag ctcgac cac ccg gtg gtg cgc tcg gcc gcc gtg cgc ccc gtc tgc 336 Gln Leu AspHis Pro Val Val Arg Ser Ala Ala Val Arg Pro Val Cys 100 105 110 ctg cccgcg cgc tcc cac ttc ttc gag ccc ggc ctg cac tgc tgg att 384 Leu Pro AlaArg Ser His Phe Phe Glu Pro Gly Leu His Cys Trp Ile 115 120 125 acg ggctgg ggc gcc ttg cgc gag ggc ggc ccc atc agc aac gct ctg 432 Thr Gly TrpGly Ala Leu Arg Glu Gly Gly Pro Ile Ser Asn Ala Leu 130 135 140 cag aaagtg gat gtg cag ttg atc cca cag gac ctg tgc agc gag gtc 480 Gln Lys ValAsp Val Gln Leu Ile Pro Gln Asp Leu Cys Ser Glu Val 145 150 155 160 tatcgc tac cag gtg acg cca cgc atg ctg tgt gcc ggc tac cgc aag 528 Tyr ArgTyr Gln Val Thr Pro Arg Met Leu Cys Ala Gly Tyr Arg Lys 165 170 175 ggcaag aag gat gcc tgt cag ggt gac tca ggt ggt ccg ctg gtg tgc 576 Gly LysLys Asp Ala Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys 180 185 190 aaggca ctc agt ggc cgc tgg ttc ctg gcg ggg ctg gtc agc tgg ggc 624 Lys AlaLeu Ser Gly Arg Trp Phe Leu Ala Gly Leu Val Ser Trp Gly 195 200 205 ctgggc tgt ggc cgg cct aac tac ttc ggc gtc tac acc cgc atc aca 672 Leu GlyCys Gly Arg Pro Asn Tyr Phe Gly Val Tyr Thr Arg Ile Thr 210 215 220 ggtgtg atc agc tgg atc cag caa gtg gtg acc tga 708 Gly Val Ile Ser Trp IleGln Gln Val Val Thr * 225 230 235 <210> SEQ ID NO 6 <211> LENGTH: 235<212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 6 Ile ValGly Gly Ala Val Ser Ser Glu Gly Glu Trp Pro Trp Gln Ala 1 5 10 15 SerLeu Gln Val Arg Gly Arg His Ile Cys Gly Gly Ala Leu Ile Ala 20 25 30 AspArg Trp Val Ile Thr Ala Ala His Cys Phe Gln Glu Asp Ser Met 35 40 45 AlaSer Thr Val Leu Trp Thr Val Phe Leu Gly Lys Val Trp Gln Asn 50 55 60 SerArg Trp Pro Gly Glu Val Ser Phe Lys Val Ser Arg Leu Leu Leu 65 70 75 80His Pro Tyr His Glu Glu Asp Ser His Asp Tyr Asp Val Ala Leu Leu 85 90 95Gln Leu Asp His Pro Val Val Arg Ser Ala Ala Val Arg Pro Val Cys 100 105110 Leu Pro Ala Arg Ser His Phe Phe Glu Pro Gly Leu His Cys Trp Ile 115120 125 Thr Gly Trp Gly Ala Leu Arg Glu Gly Gly Pro Ile Ser Asn Ala Leu130 135 140 Gln Lys Val Asp Val Gln Leu Ile Pro Gln Asp Leu Cys Ser GluVal 145 150 155 160 Tyr Arg Tyr Gln Val Thr Pro Arg Met Leu Cys Ala GlyTyr Arg Lys 165 170 175 Gly Lys Lys Asp Ala Cys Gln Gly Asp Ser Gly GlyPro Leu Val Cys 180 185 190 Lys Ala Leu Ser Gly Arg Trp Phe Leu Ala GlyLeu Val Ser Trp Gly 195 200 205 Leu Gly Cys Gly Arg Pro Asn Tyr Phe GlyVal Tyr Thr Arg Ile Thr 210 215 220 Gly Val Ile Ser Trp Ile Gln Gln ValVal Thr 225 230 235 <210> SEQ ID NO 7 <211> LENGTH: 3104 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (33)...(2441) <223> OTHER INFORMATION: Nucleic acid encodingMTSP4-L (long form) splice variant <400> SEQUENCE: 7 tcatcggccagagggtgatc agtgagcaga ag atg ccc gtg gcc gag gcc ccc 53 Met Pro Val AlaGlu Ala Pro 1 5 cag gtg gct ggc ggg cag ggg gac gga ggt gat ggc gag gaagcg gag 101 Gln Val Ala Gly Gly Gln Gly Asp Gly Gly Asp Gly Glu Glu AlaGlu 10 15 20 ccg gag ggg atg ttc aag gcc tgt gag gac tcc aag aga aaa gcccgg 149 Pro Glu Gly Met Phe Lys Ala Cys Glu Asp Ser Lys Arg Lys Ala Arg25 30 35 ggc tac ctc cgc ctg gtg ccc ctg ttt gtg ctg ctg gcc ctg ctc gtg197 Gly Tyr Leu Arg Leu Val Pro Leu Phe Val Leu Leu Ala Leu Leu Val 4045 50 55 ctg gct tcg gcg ggg gtg cta ctc tgg tat ttc cta ggg tac aag gcg245 Leu Ala Ser Ala Gly Val Leu Leu Trp Tyr Phe Leu Gly Tyr Lys Ala 6065 70 gag gtg atg gtc agc cag gtg tac tca ggc agt ctg cgt gta ctc aat293 Glu Val Met Val Ser Gln Val Tyr Ser Gly Ser Leu Arg Val Leu Asn 7580 85 cgc cac ttc tcc cag gat ctt acc cgc cgg gaa tct agt gcc ttc cgc341 Arg His Phe Ser Gln Asp Leu Thr Arg Arg Glu Ser Ser Ala Phe Arg 9095 100 agt gaa acc gcc aaa gcc cag aag atg ctc aag gag ctc atc acc agc389 Ser Glu Thr Ala Lys Ala Gln Lys Met Leu Lys Glu Leu Ile Thr Ser 105110 115 acc cgc ctg gga act tac tac aac tcc agc tcc gtc tat tcc ttt ggg437 Thr Arg Leu Gly Thr Tyr Tyr Asn Ser Ser Ser Val Tyr Ser Phe Gly 120125 130 135 gag gga ccc ctc acc tgc ttc ttc tgg ttc att ctc caa atc cccgag 485 Glu Gly Pro Leu Thr Cys Phe Phe Trp Phe Ile Leu Gln Ile Pro Glu140 145 150 cac cgc cgg ctg atg ctg agc ccc gag gtg gtg cag gca ctg ctggtg 533 His Arg Arg Leu Met Leu Ser Pro Glu Val Val Gln Ala Leu Leu Val155 160 165 gag gag ctg ctg tcc aca gtc aac agc tcg gct gcc gtc ccc tacagg 581 Glu Glu Leu Leu Ser Thr Val Asn Ser Ser Ala Ala Val Pro Tyr Arg170 175 180 gcc gag tac gaa gtg gac ccc gag ggc cta gtg atc ctg gaa gccagt 629 Ala Glu Tyr Glu Val Asp Pro Glu Gly Leu Val Ile Leu Glu Ala Ser185 190 195 gtg aaa gac ata gct gca ttg aat tcc acg ctg ggt tgt tac cgctac 677 Val Lys Asp Ile Ala Ala Leu Asn Ser Thr Leu Gly Cys Tyr Arg Tyr200 205 210 215 agc tac gtg ggc cag ggc cag gtc ctc cgg ctg aag ggg cctgac cac 725 Ser Tyr Val Gly Gln Gly Gln Val Leu Arg Leu Lys Gly Pro AspHis 220 225 230 ctg gcc tcc agc tgc ctg tgg cac ctg cag ggc ccc aag gacctc atg 773 Leu Ala Ser Ser Cys Leu Trp His Leu Gln Gly Pro Lys Asp LeuMet 235 240 245 ctc aaa ctc cgg ctg gag tgg acg ctg gca gag tgc cgg gaccga ctg 821 Leu Lys Leu Arg Leu Glu Trp Thr Leu Ala Glu Cys Arg Asp ArgLeu 250 255 260 gcc atg tat gac gtg gcc ggg ccc ctg gag aag agg ctc atcacc tcg 869 Ala Met Tyr Asp Val Ala Gly Pro Leu Glu Lys Arg Leu Ile ThrSer 265 270 275 gtg tac ggc tgc agc cgc cag gag ccc gtg gtg gag gtt ctggcg tcg 917 Val Tyr Gly Cys Ser Arg Gln Glu Pro Val Val Glu Val Leu AlaSer 280 285 290 295 ggg gcc atc atg gcg gtc gtc tgg aag aag ggc ctg cacagc tac tac 965 Gly Ala Ile Met Ala Val Val Trp Lys Lys Gly Leu His SerTyr Tyr 300 305 310 gac ccc ttc gtg ctc tcc gtg cag ccg gtg gtc ttc caggcc tgt gaa 1013 Asp Pro Phe Val Leu Ser Val Gln Pro Val Val Phe Gln AlaCys Glu 315 320 325 gtg aac ctg acg ctg gac aac agg ctc gac tcc cag ggcgtc ctc agc 1061 Val Asn Leu Thr Leu Asp Asn Arg Leu Asp Ser Gln Gly ValLeu Ser 330 335 340 acc ccg tac ttc ccc agc tac tac tcg ccc caa acc cactgc tcc tgg 1109 Thr Pro Tyr Phe Pro Ser Tyr Tyr Ser Pro Gln Thr His CysSer Trp 345 350 355 cac ctc acg gtg ccc tct ctg gac tac ggc ttg gcc ctctgg ttt gat 1157 His Leu Thr Val Pro Ser Leu Asp Tyr Gly Leu Ala Leu TrpPhe Asp 360 365 370 375 gcc tat gca ctg agg agg cag aag tat gat ttg ccgtgc acc cag ggc 1205 Ala Tyr Ala Leu Arg Arg Gln Lys Tyr Asp Leu Pro CysThr Gln Gly 380 385 390 cag tgg acg atc cag aac agg agg ctg tgt ggc ttgcgc atc ctg cag 1253 Gln Trp Thr Ile Gln Asn Arg Arg Leu Cys Gly Leu ArgIle Leu Gln 395 400 405 ccc tac gcc gag agg atc ccc gtg gtg gcc acg gccggg atc acc atc 1301 Pro Tyr Ala Glu Arg Ile Pro Val Val Ala Thr Ala GlyIle Thr Ile 410 415 420 aac ttc acc tcc cag atc tcc ctc acc ggg ccc ggtgtg cgg gtg cac 1349 Asn Phe Thr Ser Gln Ile Ser Leu Thr Gly Pro Gly ValArg Val His 425 430 435 tat ggc ttg tac aac cag tcg gac ccc tgc cct ggagag ttc ctc tgt 1397 Tyr Gly Leu Tyr Asn Gln Ser Asp Pro Cys Pro Gly GluPhe Leu Cys 440 445 450 455 tct gtg aat gga ctc tgt gtc cct gcc tgt gatggg gtc aag gac tgc 1445 Ser Val Asn Gly Leu Cys Val Pro Ala Cys Asp GlyVal Lys Asp Cys 460 465 470 ccc aac ggc ctg gat gag aga aac tgc gtt tgcaga gcc aca ttc cag 1493 Pro Asn Gly Leu Asp Glu Arg Asn Cys Val Cys ArgAla Thr Phe Gln 475 480 485 tgc aaa gag gac agc aca tgc atc tca ctg cccaag gtc tgt gat ggg 1541 Cys Lys Glu Asp Ser Thr Cys Ile Ser Leu Pro LysVal Cys Asp Gly 490 495 500 cag cct gat tgt ctc aac ggc agc gac gaa gagcag tgc cag gaa ggg 1589 Gln Pro Asp Cys Leu Asn Gly Ser Asp Glu Glu GlnCys Gln Glu Gly 505 510 515 gtg cca tgt ggg aca ttc acc ttc cag tgt gaggac cgg agc tgc gtg 1637 Val Pro Cys Gly Thr Phe Thr Phe Gln Cys Glu AspArg Ser Cys Val 520 525 530 535 aag aag ccc aac ccg cag tgt gat ggg cggccc gac tgc agg gac ggc 1685 Lys Lys Pro Asn Pro Gln Cys Asp Gly Arg ProAsp Cys Arg Asp Gly 540 545 550 tcg gat gag gag cac tgt gaa tgt ggc ctccag ggc ccc tcc agc cgc 1733 Ser Asp Glu Glu His Cys Glu Cys Gly Leu GlnGly Pro Ser Ser Arg 555 560 565 att gtt ggt gga gct gtg tcc tcc gag ggtgag tgg cca tgg cag gcc 1781 Ile Val Gly Gly Ala Val Ser Ser Glu Gly GluTrp Pro Trp Gln Ala 570 575 580 agc ctc cag gtt cgg ggt cga cac atc tgtggg ggg gcc ctc atc gct 1829 Ser Leu Gln Val Arg Gly Arg His Ile Cys GlyGly Ala Leu Ile Ala 585 590 595 gac cgc tgg gtg ata aca gct gcc cac tgcttc cag gag gac agc atg 1877 Asp Arg Trp Val Ile Thr Ala Ala His Cys PheGln Glu Asp Ser Met 600 605 610 615 gcc tcc acg gtg ctg tgg acc gtg ttcctg ggc aag gtg tgg cag aac 1925 Ala Ser Thr Val Leu Trp Thr Val Phe LeuGly Lys Val Trp Gln Asn 620 625 630 tcg cgc tgg cct gga gag gtg tcc ttcaag gtg agc cgc ctg ctc ctg 1973 Ser Arg Trp Pro Gly Glu Val Ser Phe LysVal Ser Arg Leu Leu Leu 635 640 645 cac ccg tac cac gaa gag gac agc catgac tac gac gtg gcg ctg ctg 2021 His Pro Tyr His Glu Glu Asp Ser His AspTyr Asp Val Ala Leu Leu 650 655 660 cag ctc gac cac ccg gtg gtg cgc tcggcc gcc gtg cgc ccc gtc tgc 2069 Gln Leu Asp His Pro Val Val Arg Ser AlaAla Val Arg Pro Val Cys 665 670 675 ctg ccc gcg cgc tcc cac ttc ttc gagccc ggc ctg cac tgc tgg att 2117 Leu Pro Ala Arg Ser His Phe Phe Glu ProGly Leu His Cys Trp Ile 680 685 690 695 acg ggc tgg ggc gcc ttg cgc gagggc ggc ccc atc agc aac gct ctg 2165 Thr Gly Trp Gly Ala Leu Arg Glu GlyGly Pro Ile Ser Asn Ala Leu 700 705 710 cag aaa gtg gat gtg cag ttg atccca cag gac ctg tgc agc gag gtc 2213 Gln Lys Val Asp Val Gln Leu Ile ProGln Asp Leu Cys Ser Glu Val 715 720 725 tat cgc tac cag gtg acg cca cgcatg ctg tgt gcc ggc tac cgc aag 2261 Tyr Arg Tyr Gln Val Thr Pro Arg MetLeu Cys Ala Gly Tyr Arg Lys 730 735 740 ggc aag aag gat gcc tgt cag ggtgac tca ggt ggt ccg ctg gtg tgc 2309 Gly Lys Lys Asp Ala Cys Gln Gly AspSer Gly Gly Pro Leu Val Cys 745 750 755 aag gca ctc agt ggc cgc tgg ttcctg gcg ggg ctg gtc agc tgg ggc 2357 Lys Ala Leu Ser Gly Arg Trp Phe LeuAla Gly Leu Val Ser Trp Gly 760 765 770 775 ctg ggc tgt ggc cgg cct aactac ttc ggc gtc tac acc cgc atc aca 2405 Leu Gly Cys Gly Arg Pro Asn TyrPhe Gly Val Tyr Thr Arg Ile Thr 780 785 790 ggt gtg atc agc tgg atc cagcaa gtg gtg acc tga ggaactgccc 2451 Gly Val Ile Ser Trp Ile Gln Gln ValVal Thr * 795 800 ccctgcaaag cagggcccac ctcctggact cagagagccc agggcaactgccaagcaggg 2511 ggacaagtat tctggcgggg ggtgggggag agagcaggcc ctgtggtggcaggaggggca 2571 tcttgtttcg tccctgatgt ctgtccagta tggcaggagg atgagaagtgccagcagttg 2631 ggggtcaaga cgtcccttga ggacccaggc ccacacccag cccttttgcctcccaattct 2691 ctctcctccg tccccttcct ccactgctgc ctaatgcaag gcagtggctcagcagcaaga 2751 atgctggttc tacatcccga ggagtgtctg aggtgcgccc cactctgtacagaggctgtt 2811 tgggcagcct tgcctccaga gagcagattc cagcttcgga agcccctggtctaacttggg 2871 atctgggaat ggaaggtgct cccatcggag gggaccctca gagccctggagactgccagg 2931 tgggcctgct gccactgtaa gccaaaaggt ggggaagtcc tgactccagggtccttgccc 2991 cacccctgcc tgccacctgg gccctcacag cccagaccct cactgggaggtgagctcagc 3051 tgccctttgg aataaagctg cctgatgcaa aaaaaaaaaa aaaaaaaaaaaaa 3104 <210> SEQ ID NO 8 <211> LENGTH: 802 <212> TYPE: PRT <213>ORGANISM: Homo Sapien <400> SEQUENCE: 8 Met Pro Val Ala Glu Ala Pro GlnVal Ala Gly Gly Gln Gly Asp Gly 1 5 10 15 Gly Asp Gly Glu Glu Ala GluPro Glu Gly Met Phe Lys Ala Cys Glu 20 25 30 Asp Ser Lys Arg Lys Ala ArgGly Tyr Leu Arg Leu Val Pro Leu Phe 35 40 45 Val Leu Leu Ala Leu Leu ValLeu Ala Ser Ala Gly Val Leu Leu Trp 50 55 60 Tyr Phe Leu Gly Tyr Lys AlaGlu Val Met Val Ser Gln Val Tyr Ser 65 70 75 80 Gly Ser Leu Arg Val LeuAsn Arg His Phe Ser Gln Asp Leu Thr Arg 85 90 95 Arg Glu Ser Ser Ala PheArg Ser Glu Thr Ala Lys Ala Gln Lys Met 100 105 110 Leu Lys Glu Leu IleThr Ser Thr Arg Leu Gly Thr Tyr Tyr Asn Ser 115 120 125 Ser Ser Val TyrSer Phe Gly Glu Gly Pro Leu Thr Cys Phe Phe Trp 130 135 140 Phe Ile LeuGln Ile Pro Glu His Arg Arg Leu Met Leu Ser Pro Glu 145 150 155 160 ValVal Gln Ala Leu Leu Val Glu Glu Leu Leu Ser Thr Val Asn Ser 165 170 175Ser Ala Ala Val Pro Tyr Arg Ala Glu Tyr Glu Val Asp Pro Glu Gly 180 185190 Leu Val Ile Leu Glu Ala Ser Val Lys Asp Ile Ala Ala Leu Asn Ser 195200 205 Thr Leu Gly Cys Tyr Arg Tyr Ser Tyr Val Gly Gln Gly Gln Val Leu210 215 220 Arg Leu Lys Gly Pro Asp His Leu Ala Ser Ser Cys Leu Trp HisLeu 225 230 235 240 Gln Gly Pro Lys Asp Leu Met Leu Lys Leu Arg Leu GluTrp Thr Leu 245 250 255 Ala Glu Cys Arg Asp Arg Leu Ala Met Tyr Asp ValAla Gly Pro Leu 260 265 270 Glu Lys Arg Leu Ile Thr Ser Val Tyr Gly CysSer Arg Gln Glu Pro 275 280 285 Val Val Glu Val Leu Ala Ser Gly Ala IleMet Ala Val Val Trp Lys 290 295 300 Lys Gly Leu His Ser Tyr Tyr Asp ProPhe Val Leu Ser Val Gln Pro 305 310 315 320 Val Val Phe Gln Ala Cys GluVal Asn Leu Thr Leu Asp Asn Arg Leu 325 330 335 Asp Ser Gln Gly Val LeuSer Thr Pro Tyr Phe Pro Ser Tyr Tyr Ser 340 345 350 Pro Gln Thr His CysSer Trp His Leu Thr Val Pro Ser Leu Asp Tyr 355 360 365 Gly Leu Ala LeuTrp Phe Asp Ala Tyr Ala Leu Arg Arg Gln Lys Tyr 370 375 380 Asp Leu ProCys Thr Gln Gly Gln Trp Thr Ile Gln Asn Arg Arg Leu 385 390 395 400 CysGly Leu Arg Ile Leu Gln Pro Tyr Ala Glu Arg Ile Pro Val Val 405 410 415Ala Thr Ala Gly Ile Thr Ile Asn Phe Thr Ser Gln Ile Ser Leu Thr 420 425430 Gly Pro Gly Val Arg Val His Tyr Gly Leu Tyr Asn Gln Ser Asp Pro 435440 445 Cys Pro Gly Glu Phe Leu Cys Ser Val Asn Gly Leu Cys Val Pro Ala450 455 460 Cys Asp Gly Val Lys Asp Cys Pro Asn Gly Leu Asp Glu Arg AsnCys 465 470 475 480 Val Cys Arg Ala Thr Phe Gln Cys Lys Glu Asp Ser ThrCys Ile Ser 485 490 495 Leu Pro Lys Val Cys Asp Gly Gln Pro Asp Cys LeuAsn Gly Ser Asp 500 505 510 Glu Glu Gln Cys Gln Glu Gly Val Pro Cys GlyThr Phe Thr Phe Gln 515 520 525 Cys Glu Asp Arg Ser Cys Val Lys Lys ProAsn Pro Gln Cys Asp Gly 530 535 540 Arg Pro Asp Cys Arg Asp Gly Ser AspGlu Glu His Cys Glu Cys Gly 545 550 555 560 Leu Gln Gly Pro Ser Ser ArgIle Val Gly Gly Ala Val Ser Ser Glu 565 570 575 Gly Glu Trp Pro Trp GlnAla Ser Leu Gln Val Arg Gly Arg His Ile 580 585 590 Cys Gly Gly Ala LeuIle Ala Asp Arg Trp Val Ile Thr Ala Ala His 595 600 605 Cys Phe Gln GluAsp Ser Met Ala Ser Thr Val Leu Trp Thr Val Phe 610 615 620 Leu Gly LysVal Trp Gln Asn Ser Arg Trp Pro Gly Glu Val Ser Phe 625 630 635 640 LysVal Ser Arg Leu Leu Leu His Pro Tyr His Glu Glu Asp Ser His 645 650 655Asp Tyr Asp Val Ala Leu Leu Gln Leu Asp His Pro Val Val Arg Ser 660 665670 Ala Ala Val Arg Pro Val Cys Leu Pro Ala Arg Ser His Phe Phe Glu 675680 685 Pro Gly Leu His Cys Trp Ile Thr Gly Trp Gly Ala Leu Arg Glu Gly690 695 700 Gly Pro Ile Ser Asn Ala Leu Gln Lys Val Asp Val Gln Leu IlePro 705 710 715 720 Gln Asp Leu Cys Ser Glu Val Tyr Arg Tyr Gln Val ThrPro Arg Met 725 730 735 Leu Cys Ala Gly Tyr Arg Lys Gly Lys Lys Asp AlaCys Gln Gly Asp 740 745 750 Ser Gly Gly Pro Leu Val Cys Lys Ala Leu SerGly Arg Trp Phe Leu 755 760 765 Ala Gly Leu Val Ser Trp Gly Leu Gly CysGly Arg Pro Asn Tyr Phe 770 775 780 Gly Val Tyr Thr Arg Ile Thr Gly ValIle Ser Trp Ile Gln Gln Val 785 790 795 800 Val Thr <210> SEQ ID NO 9<211> LENGTH: 2672 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (33)...(2009) <223> OTHERINFORMATION: cDNA encoding: MTSP4-S (short form) splice variant <400>SEQUENCE: 9 tcatcggcca gagggtgatc agtgagcaga ag atg ccc gtg gcc gag gccccc 53 Met Pro Val Ala Glu Ala Pro 1 5 cag gtg gct ggc ggg cag ggg gacgga ggt gat ggc gag gaa gcg gag 101 Gln Val Ala Gly Gly Gln Gly Asp GlyGly Asp Gly Glu Glu Ala Glu 10 15 20 ccg gag ggg atg ttc aag gcc tgt gaggac tcc aag aga aaa gcc cgg 149 Pro Glu Gly Met Phe Lys Ala Cys Glu AspSer Lys Arg Lys Ala Arg 25 30 35 ggc tac ctc cgc ctg gtg ccc ctg ttt gtgctg ctg gcc ctg ctc gtg 197 Gly Tyr Leu Arg Leu Val Pro Leu Phe Val LeuLeu Ala Leu Leu Val 40 45 50 55 ctg gct tcg gcg ggg gtg cta ctc tgg tatttc cta ggg tac aag gcg 245 Leu Ala Ser Ala Gly Val Leu Leu Trp Tyr PheLeu Gly Tyr Lys Ala 60 65 70 gag gtg atg gtc agc cag gtg tac tca ggc agtctg cgt gta ctc aat 293 Glu Val Met Val Ser Gln Val Tyr Ser Gly Ser LeuArg Val Leu Asn 75 80 85 cgc cac ttc tcc cag gat ctt acc cgc cgg gaa tctagt gcc ttc cgc 341 Arg His Phe Ser Gln Asp Leu Thr Arg Arg Glu Ser SerAla Phe Arg 90 95 100 agt gaa acc gcc aaa gcc cag aag atg ctc aag gagctc atc acc agc 389 Ser Glu Thr Ala Lys Ala Gln Lys Met Leu Lys Glu LeuIle Thr Ser 105 110 115 acc cgc ctg gga act tac tac aac tcc agc tcc gtctat tcc ttt ggg 437 Thr Arg Leu Gly Thr Tyr Tyr Asn Ser Ser Ser Val TyrSer Phe Gly 120 125 130 135 gtg tac ggc tgc agc cgc cag gag ccc gtg gtggag gtt ctg gcg tcg 485 Val Tyr Gly Cys Ser Arg Gln Glu Pro Val Val GluVal Leu Ala Ser 140 145 150 ggg gcc atc atg gcg gtc gtc tgg aag aag ggcctg cac agc tac tac 533 Gly Ala Ile Met Ala Val Val Trp Lys Lys Gly LeuHis Ser Tyr Tyr 155 160 165 gac ccc ttc gtg ctc tcc gtg cag ccg gtg gtcttc cag gcc tgt gaa 581 Asp Pro Phe Val Leu Ser Val Gln Pro Val Val PheGln Ala Cys Glu 170 175 180 gtg aac ctg acg ctg gac aac agg ctc gac tcccag ggc gtc ctc agc 629 Val Asn Leu Thr Leu Asp Asn Arg Leu Asp Ser GlnGly Val Leu Ser 185 190 195 acc ccg tac ttc ccc agc tac tac tcg ccc caaacc cac tgc tcc tgg 677 Thr Pro Tyr Phe Pro Ser Tyr Tyr Ser Pro Gln ThrHis Cys Ser Trp 200 205 210 215 cac ctc acg gtg ccc tct ctg gac tac ggcttg gcc ctc tgg ttt gat 725 His Leu Thr Val Pro Ser Leu Asp Tyr Gly LeuAla Leu Trp Phe Asp 220 225 230 gcc tat gca ctg agg agg cag aag tat gatttg ccg tgc acc cag ggc 773 Ala Tyr Ala Leu Arg Arg Gln Lys Tyr Asp LeuPro Cys Thr Gln Gly 235 240 245 cag tgg acg atc cag aac agg agg ctg tgtggc ttg cgc atc ctg cag 821 Gln Trp Thr Ile Gln Asn Arg Arg Leu Cys GlyLeu Arg Ile Leu Gln 250 255 260 ccc tac gcc gag agg atc ccc gtg gtg gccacg gcc ggg atc acc atc 869 Pro Tyr Ala Glu Arg Ile Pro Val Val Ala ThrAla Gly Ile Thr Ile 265 270 275 aac ttc acc tcc cag atc tcc ctc acc gggccc ggt gtg cgg gtg cac 917 Asn Phe Thr Ser Gln Ile Ser Leu Thr Gly ProGly Val Arg Val His 280 285 290 295 tat ggc ttg tac aac cag tcg gac ccctgc cct gga gag ttc ctc tgt 965 Tyr Gly Leu Tyr Asn Gln Ser Asp Pro CysPro Gly Glu Phe Leu Cys 300 305 310 tct gtg aat gga ctc tgt gtc cct gcctgt gat ggg gtc aag gac tgc 1013 Ser Val Asn Gly Leu Cys Val Pro Ala CysAsp Gly Val Lys Asp Cys 315 320 325 ccc aac ggc ctg gat gag aga aac tgcgtt tgc aga gcc aca ttc cag 1061 Pro Asn Gly Leu Asp Glu Arg Asn Cys ValCys Arg Ala Thr Phe Gln 330 335 340 tgc aaa gag gac agc aca tgc atc tcactg ccc aag gtc tgt gat ggg 1109 Cys Lys Glu Asp Ser Thr Cys Ile Ser LeuPro Lys Val Cys Asp Gly 345 350 355 cag cct gat tgt ctc aac ggc agc gacgaa gag cag tgc cag gaa ggg 1157 Gln Pro Asp Cys Leu Asn Gly Ser Asp GluGlu Gln Cys Gln Glu Gly 360 365 370 375 gtg cca tgt ggg aca ttc acc ttccag tgt gag gac cgg agc tgc gtg 1205 Val Pro Cys Gly Thr Phe Thr Phe GlnCys Glu Asp Arg Ser Cys Val 380 385 390 aag aag ccc aac ccg cag tgt gatggg cgg ccc gac tgc agg gac ggc 1253 Lys Lys Pro Asn Pro Gln Cys Asp GlyArg Pro Asp Cys Arg Asp Gly 395 400 405 tcg gat gag gag cac tgt gaa tgtggc ctc cag ggc ccc tcc agc cgc 1301 Ser Asp Glu Glu His Cys Glu Cys GlyLeu Gln Gly Pro Ser Ser Arg 410 415 420 att gtt ggt gga gct gtg tcc tccgag ggt gag tgg cca tgg cag gcc 1349 Ile Val Gly Gly Ala Val Ser Ser GluGly Glu Trp Pro Trp Gln Ala 425 430 435 agc ctc cag gtt cgg ggt cga cacatc tgt ggg ggg gcc ctc atc gct 1397 Ser Leu Gln Val Arg Gly Arg His IleCys Gly Gly Ala Leu Ile Ala 440 445 450 455 gac cgc tgg gtg ata aca gctgcc cac tgc ttc cag gag gac agc atg 1445 Asp Arg Trp Val Ile Thr Ala AlaHis Cys Phe Gln Glu Asp Ser Met 460 465 470 gcc tcc acg gtg ctg tgg accgtg ttc ctg ggc aag gtg tgg cag aac 1493 Ala Ser Thr Val Leu Trp Thr ValPhe Leu Gly Lys Val Trp Gln Asn 475 480 485 tcg cgc tgg cct gga gag gtgtcc ttc aag gtg agc cgc ctg ctc ctg 1541 Ser Arg Trp Pro Gly Glu Val SerPhe Lys Val Ser Arg Leu Leu Leu 490 495 500 cac ccg tac cac gaa gag gacagc cat gac tac gac gtg gcg ctg ctg 1589 His Pro Tyr His Glu Glu Asp SerHis Asp Tyr Asp Val Ala Leu Leu 505 510 515 cag ctc gac cac ccg gtg gtgcgc tcg gcc gcc gtg cgc ccc gtc tgc 1637 Gln Leu Asp His Pro Val Val ArgSer Ala Ala Val Arg Pro Val Cys 520 525 530 535 ctg ccc gcg cgc tcc cacttc ttc gag ccc ggc ctg cac tgc tgg att 1685 Leu Pro Ala Arg Ser His PhePhe Glu Pro Gly Leu His Cys Trp Ile 540 545 550 acg ggc tgg ggc gcc ttgcgc gag ggc ggc ccc atc agc aac gct ctg 1733 Thr Gly Trp Gly Ala Leu ArgGlu Gly Gly Pro Ile Ser Asn Ala Leu 555 560 565 cag aaa gtg gat gtg cagttg atc cca cag gac ctg tgc agc gag gtc 1781 Gln Lys Val Asp Val Gln LeuIle Pro Gln Asp Leu Cys Ser Glu Val 570 575 580 tat cgc tac cag gtg acgcca cgc atg ctg tgt gcc ggc tac cgc aag 1829 Tyr Arg Tyr Gln Val Thr ProArg Met Leu Cys Ala Gly Tyr Arg Lys 585 590 595 ggc aag aag gat gcc tgtcag ggt gac tca ggt ggt ccg ctg gtg tgc 1877 Gly Lys Lys Asp Ala Cys GlnGly Asp Ser Gly Gly Pro Leu Val Cys 600 605 610 615 aag gca ctc agt ggccgc tgg ttc ctg gcg ggg ctg gtc agc tgg ggc 1925 Lys Ala Leu Ser Gly ArgTrp Phe Leu Ala Gly Leu Val Ser Trp Gly 620 625 630 ctg ggc tgt ggc cggcct aac tac ttc ggc gtc tac acc cgc atc aca 1973 Leu Gly Cys Gly Arg ProAsn Tyr Phe Gly Val Tyr Thr Arg Ile Thr 635 640 645 ggt gtg atc agc tggatc cag caa gtg gtg acc tga ggaactgccc 2019 Gly Val Ile Ser Trp Ile GlnGln Val Val Thr * 650 655 ccctgcaaag cagggcccac ctcctggact cagagagcccagggcaactg ccaagcaggg 2079 ggacaagtat tctggcgggg ggtgggggag agagcaggccctgtggtggc aggaggggca 2139 tcttgtttcg tccctgatgt ctgtccagta tggcaggaggatgagaagtg ccagcagttg 2199 ggggtcaaga cgtcccttga ggacccaggc ccacacccagcccttttgcc tcccaattct 2259 ctctcctccg tccccttcct ccactgctgc ctaatgcaaggcagtggctc agcagcaaga 2319 atgctggttc tacatcccga ggagtgtctg aggtgcgccccactctgtac agaggctgtt 2379 tgggcagcct tgcctccaga gagcagattc cagcttcggaagcccctggt ctaacttggg 2439 atctgggaat ggaaggtgct cccatcggag gggaccctcagagccctgga gactgccagg 2499 tgggcctgct gccactgtaa gccaaaaggt ggggaagtcctgactccagg gtccttgccc 2559 cacccctgcc tgccacctgg gccctcacag cccagaccctcactgggagg tgagctcagc 2619 tgccctttgg aataaagctg cctgatgcaa aaaaaaaaaaaaaaaaaaaa aaa 2672 <210> SEQ ID NO 10 <211> LENGTH: 658 <212> TYPE: PRT<213> ORGANISM: Homo Sapien <400> SEQUENCE: 10 Met Pro Val Ala Glu AlaPro Gln Val Ala Gly Gly Gln Gly Asp Gly 1 5 10 15 Gly Asp Gly Glu GluAla Glu Pro Glu Gly Met Phe Lys Ala Cys Glu 20 25 30 Asp Ser Lys Arg LysAla Arg Gly Tyr Leu Arg Leu Val Pro Leu Phe 35 40 45 Val Leu Leu Ala LeuLeu Val Leu Ala Ser Ala Gly Val Leu Leu Trp 50 55 60 Tyr Phe Leu Gly TyrLys Ala Glu Val Met Val Ser Gln Val Tyr Ser 65 70 75 80 Gly Ser Leu ArgVal Leu Asn Arg His Phe Ser Gln Asp Leu Thr Arg 85 90 95 Arg Glu Ser SerAla Phe Arg Ser Glu Thr Ala Lys Ala Gln Lys Met 100 105 110 Leu Lys GluLeu Ile Thr Ser Thr Arg Leu Gly Thr Tyr Tyr Asn Ser 115 120 125 Ser SerVal Tyr Ser Phe Gly Val Tyr Gly Cys Ser Arg Gln Glu Pro 130 135 140 ValVal Glu Val Leu Ala Ser Gly Ala Ile Met Ala Val Val Trp Lys 145 150 155160 Lys Gly Leu His Ser Tyr Tyr Asp Pro Phe Val Leu Ser Val Gln Pro 165170 175 Val Val Phe Gln Ala Cys Glu Val Asn Leu Thr Leu Asp Asn Arg Leu180 185 190 Asp Ser Gln Gly Val Leu Ser Thr Pro Tyr Phe Pro Ser Tyr TyrSer 195 200 205 Pro Gln Thr His Cys Ser Trp His Leu Thr Val Pro Ser LeuAsp Tyr 210 215 220 Gly Leu Ala Leu Trp Phe Asp Ala Tyr Ala Leu Arg ArgGln Lys Tyr 225 230 235 240 Asp Leu Pro Cys Thr Gln Gly Gln Trp Thr IleGln Asn Arg Arg Leu 245 250 255 Cys Gly Leu Arg Ile Leu Gln Pro Tyr AlaGlu Arg Ile Pro Val Val 260 265 270 Ala Thr Ala Gly Ile Thr Ile Asn PheThr Ser Gln Ile Ser Leu Thr 275 280 285 Gly Pro Gly Val Arg Val His TyrGly Leu Tyr Asn Gln Ser Asp Pro 290 295 300 Cys Pro Gly Glu Phe Leu CysSer Val Asn Gly Leu Cys Val Pro Ala 305 310 315 320 Cys Asp Gly Val LysAsp Cys Pro Asn Gly Leu Asp Glu Arg Asn Cys 325 330 335 Val Cys Arg AlaThr Phe Gln Cys Lys Glu Asp Ser Thr Cys Ile Ser 340 345 350 Leu Pro LysVal Cys Asp Gly Gln Pro Asp Cys Leu Asn Gly Ser Asp 355 360 365 Glu GluGln Cys Gln Glu Gly Val Pro Cys Gly Thr Phe Thr Phe Gln 370 375 380 CysGlu Asp Arg Ser Cys Val Lys Lys Pro Asn Pro Gln Cys Asp Gly 385 390 395400 Arg Pro Asp Cys Arg Asp Gly Ser Asp Glu Glu His Cys Glu Cys Gly 405410 415 Leu Gln Gly Pro Ser Ser Arg Ile Val Gly Gly Ala Val Ser Ser Glu420 425 430 Gly Glu Trp Pro Trp Gln Ala Ser Leu Gln Val Arg Gly Arg HisIle 435 440 445 Cys Gly Gly Ala Leu Ile Ala Asp Arg Trp Val Ile Thr AlaAla His 450 455 460 Cys Phe Gln Glu Asp Ser Met Ala Ser Thr Val Leu TrpThr Val Phe 465 470 475 480 Leu Gly Lys Val Trp Gln Asn Ser Arg Trp ProGly Glu Val Ser Phe 485 490 495 Lys Val Ser Arg Leu Leu Leu His Pro TyrHis Glu Glu Asp Ser His 500 505 510 Asp Tyr Asp Val Ala Leu Leu Gln LeuAsp His Pro Val Val Arg Ser 515 520 525 Ala Ala Val Arg Pro Val Cys LeuPro Ala Arg Ser His Phe Phe Glu 530 535 540 Pro Gly Leu His Cys Trp IleThr Gly Trp Gly Ala Leu Arg Glu Gly 545 550 555 560 Gly Pro Ile Ser AsnAla Leu Gln Lys Val Asp Val Gln Leu Ile Pro 565 570 575 Gln Asp Leu CysSer Glu Val Tyr Arg Tyr Gln Val Thr Pro Arg Met 580 585 590 Leu Cys AlaGly Tyr Arg Lys Gly Lys Lys Asp Ala Cys Gln Gly Asp 595 600 605 Ser GlyGly Pro Leu Val Cys Lys Ala Leu Ser Gly Arg Trp Phe Leu 610 615 620 AlaGly Leu Val Ser Trp Gly Leu Gly Cys Gly Arg Pro Asn Tyr Phe 625 630 635640 Gly Val Tyr Thr Arg Ile Thr Gly Val Ile Ser Trp Ile Gln Gln Val 645650 655 Val Thr <210> SEQ ID NO 11 <211> LENGTH: 1656 <212> TYPE: DNA<213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (268)...(1629) <223> OTHER INFORMATION: Nucleic acid encodinga transmembrane serine protease (MTSP-6) protein <400> SEQUENCE: 11cgcccgggca ggtcagtaac actgtggcct actatctctt ccgtggtgcc atctacattt 60ttgggactcg ggaattatga ctgtttttgg ttaatcgata ctgaatgcgc tttgtgtgga 120ctgtcgaatt tcaaagattt accgtatgac caagatgcac ctgatgctac aagtataaat 180aggggaacaa atgctttctg ttcttcctcg gctaaggagg tagaggtgga ggcggagccg 240gatgtcagag gtcctgaaat agtcacc atg ggg gaa aat gat ccg cct gct gtt 294Met Gly Glu Asn Asp Pro Pro Ala Val 1 5 gaa gcc ccc ttc tca ttc cga tcgctt ttt ggc ctt gat gat ttg aaa 342 Glu Ala Pro Phe Ser Phe Arg Ser LeuPhe Gly Leu Asp Asp Leu Lys 10 15 20 25 ata agt cct gtt gca cca gat gcagat gct gtt gct gca cag atc ctg 390 Ile Ser Pro Val Ala Pro Asp Ala AspAla Val Ala Ala Gln Ile Leu 30 35 40 tca ctg ctg cca ttg aag ttt ttt ccaatc atc gtc att ggg atc att 438 Ser Leu Leu Pro Leu Lys Phe Phe Pro IleIle Val Ile Gly Ile Ile 45 50 55 gca ttg ata tta gca ctg gcc att ggt ctgggc atc cac ttc gac tgc 486 Ala Leu Ile Leu Ala Leu Ala Ile Gly Leu GlyIle His Phe Asp Cys 60 65 70 tca ggg aag tac aga tgt cgc tca tcc ttt aagtgt atc gag ctg ata 534 Ser Gly Lys Tyr Arg Cys Arg Ser Ser Phe Lys CysIle Glu Leu Ile 75 80 85 gct cga tgt gac gga gtc tcg gat tgc aaa gac ggggag gac gag tac 582 Ala Arg Cys Asp Gly Val Ser Asp Cys Lys Asp Gly GluAsp Glu Tyr 90 95 100 105 cgc tgt gtc cgg gtg ggt ggt cag aat gcc gtgctc cag gtg ttc aca 630 Arg Cys Val Arg Val Gly Gly Gln Asn Ala Val LeuGln Val Phe Thr 110 115 120 gct gct tcg tgg aag acc atg tgc tcc gat gactgg aag ggt cac tac 678 Ala Ala Ser Trp Lys Thr Met Cys Ser Asp Asp TrpLys Gly His Tyr 125 130 135 gca aat gtt gcc tgt gcc caa ctg ggt ttc ccaagc tat gta agt tca 726 Ala Asn Val Ala Cys Ala Gln Leu Gly Phe Pro SerTyr Val Ser Ser 140 145 150 gat aac ctc aga gtg agc tcg cta gag ggg cagttc cgg gag gag ttt 774 Asp Asn Leu Arg Val Ser Ser Leu Glu Gly Gln PheArg Glu Glu Phe 155 160 165 gtg tcc atc gat cac ctc ttg cca gat gac aaggtg act gca tta cac 822 Val Ser Ile Asp His Leu Leu Pro Asp Asp Lys ValThr Ala Leu His 170 175 180 185 cac tca gta tat gtg agg gag gga tgt gcctct ggc cac gtg gtt acc 870 His Ser Val Tyr Val Arg Glu Gly Cys Ala SerGly His Val Val Thr 190 195 200 ttg cag tgc aca gcc tgt ggt cat aga aggggc tac agc tca cgc atc 918 Leu Gln Cys Thr Ala Cys Gly His Arg Arg GlyTyr Ser Ser Arg Ile 205 210 215 gtg ggt gga aac atg tcc ttg ctc tcg cagtgg ccc tgg cag gcc agc 966 Val Gly Gly Asn Met Ser Leu Leu Ser Gln TrpPro Trp Gln Ala Ser 220 225 230 ctt cag ttc cag ggc tac cac ctg tgc gggggc tct gtc atc acg ccc 1014 Leu Gln Phe Gln Gly Tyr His Leu Cys Gly GlySer Val Ile Thr Pro 235 240 245 ctg tgg atc atc act gct gca cac tgt gtttat gac ttg tac ctc ccc 1062 Leu Trp Ile Ile Thr Ala Ala His Cys Val TyrAsp Leu Tyr Leu Pro 250 255 260 265 aag tca tgg acc atc cag gtg ggt ctagtt tcc ctg ttg gac aat cca 1110 Lys Ser Trp Thr Ile Gln Val Gly Leu ValSer Leu Leu Asp Asn Pro 270 275 280 gcc cca tcc cac ttg gtg gag aag attgtc tac cac agc aag tac aag 1158 Ala Pro Ser His Leu Val Glu Lys Ile ValTyr His Ser Lys Tyr Lys 285 290 295 cca aag agg ctg ggc aat gac atc gccctt atg aag ctg gcc ggg cca 1206 Pro Lys Arg Leu Gly Asn Asp Ile Ala LeuMet Lys Leu Ala Gly Pro 300 305 310 ctc acg ttc aat gaa atg atc cag cctgtg tgc ctg ccc aac tct gaa 1254 Leu Thr Phe Asn Glu Met Ile Gln Pro ValCys Leu Pro Asn Ser Glu 315 320 325 gag aac ttc ccc gat gga aaa gtg tgctgg acg tca gga tgg ggg gcc 1302 Glu Asn Phe Pro Asp Gly Lys Val Cys TrpThr Ser Gly Trp Gly Ala 330 335 340 345 aca gag gat gga ggt gac gcc tcccct gtc ctg aac cac gcg gcc gtc 1350 Thr Glu Asp Gly Gly Asp Ala Ser ProVal Leu Asn His Ala Ala Val 350 355 360 cct ttg att tcc aac aag atc tgcaac cac agg gac gtg tac ggt ggc 1398 Pro Leu Ile Ser Asn Lys Ile Cys AsnHis Arg Asp Val Tyr Gly Gly 365 370 375 atc atc tcc ccc tcc atg ctc tgcgcg ggc tac ctg acg ggt ggc gtg 1446 Ile Ile Ser Pro Ser Met Leu Cys AlaGly Tyr Leu Thr Gly Gly Val 380 385 390 gac agc tgc cag ggg gac agc gggggg ccc ctg gtg tgt caa gag agg 1494 Asp Ser Cys Gln Gly Asp Ser Gly GlyPro Leu Val Cys Gln Glu Arg 395 400 405 agg ctg tgg aag tta gtg gga gcgacc agc ttt ggc atc ggc tgc gca 1542 Arg Leu Trp Lys Leu Val Gly Ala ThrSer Phe Gly Ile Gly Cys Ala 410 415 420 425 gag gtg aac aag cct ggg gtgtac acc cgt gtc acc tcc ttc ctg gac 1590 Glu Val Asn Lys Pro Gly Val TyrThr Arg Val Thr Ser Phe Leu Asp 430 435 440 tgg atc cac gag cag atg gagaga gac cta aaa acc tga agaggaaggg 1639 Trp Ile His Glu Gln Met Glu ArgAsp Leu Lys Thr * 445 450 gataagtagc cacctga 1656 <210> SEQ ID NO 12<211> LENGTH: 453 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400>SEQUENCE: 12 Met Gly Glu Asn Asp Pro Pro Ala Val Glu Ala Pro Phe Ser PheArg 1 5 10 15 Ser Leu Phe Gly Leu Asp Asp Leu Lys Ile Ser Pro Val AlaPro Asp 20 25 30 Ala Asp Ala Val Ala Ala Gln Ile Leu Ser Leu Leu Pro LeuLys Phe 35 40 45 Phe Pro Ile Ile Val Ile Gly Ile Ile Ala Leu Ile Leu AlaLeu Ala 50 55 60 Ile Gly Leu Gly Ile His Phe Asp Cys Ser Gly Lys Tyr ArgCys Arg 65 70 75 80 Ser Ser Phe Lys Cys Ile Glu Leu Ile Ala Arg Cys AspGly Val Ser 85 90 95 Asp Cys Lys Asp Gly Glu Asp Glu Tyr Arg Cys Val ArgVal Gly Gly 100 105 110 Gln Asn Ala Val Leu Gln Val Phe Thr Ala Ala SerTrp Lys Thr Met 115 120 125 Cys Ser Asp Asp Trp Lys Gly His Tyr Ala AsnVal Ala Cys Ala Gln 130 135 140 Leu Gly Phe Pro Ser Tyr Val Ser Ser AspAsn Leu Arg Val Ser Ser 145 150 155 160 Leu Glu Gly Gln Phe Arg Glu GluPhe Val Ser Ile Asp His Leu Leu 165 170 175 Pro Asp Asp Lys Val Thr AlaLeu His His Ser Val Tyr Val Arg Glu 180 185 190 Gly Cys Ala Ser Gly HisVal Val Thr Leu Gln Cys Thr Ala Cys Gly 195 200 205 His Arg Arg Gly TyrSer Ser Arg Ile Val Gly Gly Asn Met Ser Leu 210 215 220 Leu Ser Gln TrpPro Trp Gln Ala Ser Leu Gln Phe Gln Gly Tyr His 225 230 235 240 Leu CysGly Gly Ser Val Ile Thr Pro Leu Trp Ile Ile Thr Ala Ala 245 250 255 HisCys Val Tyr Asp Leu Tyr Leu Pro Lys Ser Trp Thr Ile Gln Val 260 265 270Gly Leu Val Ser Leu Leu Asp Asn Pro Ala Pro Ser His Leu Val Glu 275 280285 Lys Ile Val Tyr His Ser Lys Tyr Lys Pro Lys Arg Leu Gly Asn Asp 290295 300 Ile Ala Leu Met Lys Leu Ala Gly Pro Leu Thr Phe Asn Glu Met Ile305 310 315 320 Gln Pro Val Cys Leu Pro Asn Ser Glu Glu Asn Phe Pro AspGly Lys 325 330 335 Val Cys Trp Thr Ser Gly Trp Gly Ala Thr Glu Asp GlyGly Asp Ala 340 345 350 Ser Pro Val Leu Asn His Ala Ala Val Pro Leu IleSer Asn Lys Ile 355 360 365 Cys Asn His Arg Asp Val Tyr Gly Gly Ile IleSer Pro Ser Met Leu 370 375 380 Cys Ala Gly Tyr Leu Thr Gly Gly Val AspSer Cys Gln Gly Asp Ser 385 390 395 400 Gly Gly Pro Leu Val Cys Gln GluArg Arg Leu Trp Lys Leu Val Gly 405 410 415 Ala Thr Ser Phe Gly Ile GlyCys Ala Glu Val Asn Lys Pro Gly Val 420 425 430 Tyr Thr Arg Val Thr SerPhe Leu Asp Trp Ile His Glu Gln Met Glu 435 440 445 Arg Asp Leu Lys Thr450 <210> SEQ ID NO 13 <211> LENGTH: 2100 <212> TYPE: DNA <213>ORGANISM: Homo sapien <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(45)...(1361) <223> OTHER INFORMATION: Nucleic acid encoding MTSP7 <400>SEQUENCE: 13 agatcagatg gcgactgaat agaagctgcc ccagtcctgg gttc atg atgtac aca 56 Met Met Tyr Thr 1 cct gtt gaa ttt tca gaa gct gaa ttc tca cgagct gaa tat caa aga 104 Pro Val Glu Phe Ser Glu Ala Glu Phe Ser Arg AlaGlu Tyr Gln Arg 5 10 15 20 aag cag caa ttt tgg gac tca gta cgg cta gctctt ttc aca tta gca 152 Lys Gln Gln Phe Trp Asp Ser Val Arg Leu Ala LeuPhe Thr Leu Ala 25 30 35 att gta gca atc ata gga att gca att ggt att gttact cat ttt gtt 200 Ile Val Ala Ile Ile Gly Ile Ala Ile Gly Ile Val ThrHis Phe Val 40 45 50 gtt gag gat gat aag tct ttc tat tac ctt gcc tct tttaaa gtc aca 248 Val Glu Asp Asp Lys Ser Phe Tyr Tyr Leu Ala Ser Phe LysVal Thr 55 60 65 aat atc aaa tat aaa gaa aat tat ggc ata aga tct tca agagag ttt 296 Asn Ile Lys Tyr Lys Glu Asn Tyr Gly Ile Arg Ser Ser Arg GluPhe 70 75 80 ata gaa agg agt cat cag att gaa aga atg atg tct agg ata tttcga 344 Ile Glu Arg Ser His Gln Ile Glu Arg Met Met Ser Arg Ile Phe Arg85 90 95 100 cat tct tct gta ggc ggt cga ttt atc aaa tct cat gtt atc aaatta 392 His Ser Ser Val Gly Gly Arg Phe Ile Lys Ser His Val Ile Lys Leu105 110 115 agt cca gat gaa caa ggt gtg gat att ctt ata gtg ctc ata tttcga 440 Ser Pro Asp Glu Gln Gly Val Asp Ile Leu Ile Val Leu Ile Phe Arg120 125 130 tac cca tct act gat agt gct gaa caa atc aag aaa aaa att gaaaag 488 Tyr Pro Ser Thr Asp Ser Ala Glu Gln Ile Lys Lys Lys Ile Glu Lys135 140 145 gct tta tat caa agt ttg aag acc aaa caa ttg tct ttg acc ataaac 536 Ala Leu Tyr Gln Ser Leu Lys Thr Lys Gln Leu Ser Leu Thr Ile Asn150 155 160 aaa cca tca ttt aga ctc aca cct att gac agc aaa aag atg aggaat 584 Lys Pro Ser Phe Arg Leu Thr Pro Ile Asp Ser Lys Lys Met Arg Asn165 170 175 180 ctt ctc aac agt cgc tgt gga ata agg atg aca tct tca aacatg cca 632 Leu Leu Asn Ser Arg Cys Gly Ile Arg Met Thr Ser Ser Asn MetPro 185 190 195 tta cca gca tcc tct tct act caa aga att gtc caa gga agggaa aca 680 Leu Pro Ala Ser Ser Ser Thr Gln Arg Ile Val Gln Gly Arg GluThr 200 205 210 gct atg gaa ggg gaa tgg cca tgg cag gcc agc ctc cag ctcata ggg 728 Ala Met Glu Gly Glu Trp Pro Trp Gln Ala Ser Leu Gln Leu IleGly 215 220 225 tca ggc cat cag tgt gga gcc agc ctc atc agt aac aca tggctg ctc 776 Ser Gly His Gln Cys Gly Ala Ser Leu Ile Ser Asn Thr Trp LeuLeu 230 235 240 aca gca gct cac tgc ttt tgg aaa aat aaa gac cca act caatgg att 824 Thr Ala Ala His Cys Phe Trp Lys Asn Lys Asp Pro Thr Gln TrpIle 245 250 255 260 gct act ttt ggt gca act ata aca cca ccc gca gtg aaacga aat gtg 872 Ala Thr Phe Gly Ala Thr Ile Thr Pro Pro Ala Val Lys ArgAsn Val 265 270 275 agg aaa att att ctt cat gag aat tac cat aga gaa acaaat gaa aat 920 Arg Lys Ile Ile Leu His Glu Asn Tyr His Arg Glu Thr AsnGlu Asn 280 285 290 gac att gct ttg gtt cag ctc tct act gga gtt gag ttttca aat ata 968 Asp Ile Ala Leu Val Gln Leu Ser Thr Gly Val Glu Phe SerAsn Ile 295 300 305 gtc cag aga gtt tgc ctc cca gac tca tct ata aag ttgcca cct aaa 1016 Val Gln Arg Val Cys Leu Pro Asp Ser Ser Ile Lys Leu ProPro Lys 310 315 320 aca agt gtg ttc gtc aca gga ttt gga tcc att gta gatgat gga cct 1064 Thr Ser Val Phe Val Thr Gly Phe Gly Ser Ile Val Asp AspGly Pro 325 330 335 340 ata caa aat aca ctt cgg caa gcc aga gtg gaa accata agc act gat 1112 Ile Gln Asn Thr Leu Arg Gln Ala Arg Val Glu Thr IleSer Thr Asp 345 350 355 gtg tgt aac aga aag gat gtg tat gat ggc ctg ataact cca gga atg 1160 Val Cys Asn Arg Lys Asp Val Tyr Asp Gly Leu Ile ThrPro Gly Met 360 365 370 tta tgt gct gga ttc atg gaa gga aaa ata gat gcatgt aag gga gat 1208 Leu Cys Ala Gly Phe Met Glu Gly Lys Ile Asp Ala CysLys Gly Asp 375 380 385 tct ggt gga cct ctg gtt tat gat aat cat gac atctgg tac att gta 1256 Ser Gly Gly Pro Leu Val Tyr Asp Asn His Asp Ile TrpTyr Ile Val 390 395 400 ggt ata gta agt tgg gga caa tca tgt gca ctt cccaaa aaa cct gga 1304 Gly Ile Val Ser Trp Gly Gln Ser Cys Ala Leu Pro LysLys Pro Gly 405 410 415 420 gtc tac acc aga gta act aag tat cga gat tggatt gcc tca aag act 1352 Val Tyr Thr Arg Val Thr Lys Tyr Arg Asp Trp IleAla Ser Lys Thr 425 430 435 ggt atg tag tgtggattgt ccatgagtta tacacatggcacacagagct 1401 Gly Met * gatactcctg cgtattttgt attgtttaaa ttcatttactttggattagt gcttttgcta 1461 gatgtcaaga agcccttcag acccagacaa atctaatatcctgaggtggc ctttacatac 1521 gtaggaccaa accctctcta ccatgaggga agaagacacagcaaatgaca gacagcacct 1581 attccttact cacaagggaa actgcttgtg atacttcctaataagataaa taagtggttt 1641 ccctcaattg aagacaggaa catcattttc cacaggatatgaagagctgc cagtaatgcc 1701 aaaatcttac ctcatataat acctggagca tgtgagattcttctagtgaa aaagaacagt 1761 cttccctgaa gactcagggc ttcaacattc tagaactgataagtggacct tcagtgtgca 1821 agaatggaga agcatgggat ttgcattatg acttgaactgggcttatatc taataataca 1881 gagcactatc actaacctca acagttgaca ttttaaaagtttttaaatgt atctgaactt 1941 gctgttaaca cagtgttata actcaagcac tagcttcaggaagcatgttg tgttgttaag 2001 aagcttttct gatttattct ttaacagcat cttgccatctatatgttagt agcagttggc 2061 ccagaaagga caaaaaaaaa aaaaaaaaaa aaaaaaaaa2100 <210> SEQ ID NO 14 <211> LENGTH: 438 <212> TYPE: PRT <213>ORGANISM: Homo sapien <400> SEQUENCE: 14 Met Met Tyr Thr Pro Val Glu PheSer Glu Ala Glu Phe Ser Arg Ala 1 5 10 15 Glu Tyr Gln Arg Lys Gln GlnPhe Trp Asp Ser Val Arg Leu Ala Leu 20 25 30 Phe Thr Leu Ala Ile Val AlaIle Ile Gly Ile Ala Ile Gly Ile Val 35 40 45 Thr His Phe Val Val Glu AspAsp Lys Ser Phe Tyr Tyr Leu Ala Ser 50 55 60 Phe Lys Val Thr Asn Ile LysTyr Lys Glu Asn Tyr Gly Ile Arg Ser 65 70 75 80 Ser Arg Glu Phe Ile GluArg Ser His Gln Ile Glu Arg Met Met Ser 85 90 95 Arg Ile Phe Arg His SerSer Val Gly Gly Arg Phe Ile Lys Ser His 100 105 110 Val Ile Lys Leu SerPro Asp Glu Gln Gly Val Asp Ile Leu Ile Val 115 120 125 Leu Ile Phe ArgTyr Pro Ser Thr Asp Ser Ala Glu Gln Ile Lys Lys 130 135 140 Lys Ile GluLys Ala Leu Tyr Gln Ser Leu Lys Thr Lys Gln Leu Ser 145 150 155 160 LeuThr Ile Asn Lys Pro Ser Phe Arg Leu Thr Pro Ile Asp Ser Lys 165 170 175Lys Met Arg Asn Leu Leu Asn Ser Arg Cys Gly Ile Arg Met Thr Ser 180 185190 Ser Asn Met Pro Leu Pro Ala Ser Ser Ser Thr Gln Arg Ile Val Gln 195200 205 Gly Arg Glu Thr Ala Met Glu Gly Glu Trp Pro Trp Gln Ala Ser Leu210 215 220 Gln Leu Ile Gly Ser Gly His Gln Cys Gly Ala Ser Leu Ile SerAsn 225 230 235 240 Thr Trp Leu Leu Thr Ala Ala His Cys Phe Trp Lys AsnLys Asp Pro 245 250 255 Thr Gln Trp Ile Ala Thr Phe Gly Ala Thr Ile ThrPro Pro Ala Val 260 265 270 Lys Arg Asn Val Arg Lys Ile Ile Leu His GluAsn Tyr His Arg Glu 275 280 285 Thr Asn Glu Asn Asp Ile Ala Leu Val GlnLeu Ser Thr Gly Val Glu 290 295 300 Phe Ser Asn Ile Val Gln Arg Val CysLeu Pro Asp Ser Ser Ile Lys 305 310 315 320 Leu Pro Pro Lys Thr Ser ValPhe Val Thr Gly Phe Gly Ser Ile Val 325 330 335 Asp Asp Gly Pro Ile GlnAsn Thr Leu Arg Gln Ala Arg Val Glu Thr 340 345 350 Ile Ser Thr Asp ValCys Asn Arg Lys Asp Val Tyr Asp Gly Leu Ile 355 360 365 Thr Pro Gly MetLeu Cys Ala Gly Phe Met Glu Gly Lys Ile Asp Ala 370 375 380 Cys Lys GlyAsp Ser Gly Gly Pro Leu Val Tyr Asp Asn His Asp Ile 385 390 395 400 TrpTyr Ile Val Gly Ile Val Ser Trp Gly Gln Ser Cys Ala Leu Pro 405 410 415Lys Lys Pro Gly Val Tyr Thr Arg Val Thr Lys Tyr Arg Asp Trp Ile 420 425430 Ala Ser Lys Thr Gly Met 435 <210> SEQ ID NO 15 <211> LENGTH: 702<212> TYPE: DNA <213> ORGANISM: Homo sapien <220> FEATURE: <221>NAME/KEY: CDS <222> LOCATION: (1)...(702) <223> OTHER INFORMATION:Nucleotide sequence encoding MTSP-7 Protease Domain <400> SEQUENCE: 15att gtc caa gga agg gaa aca gct atg gaa ggg gaa tgg cca tgg cag 48 IleVal Gln Gly Arg Glu Thr Ala Met Glu Gly Glu Trp Pro Trp Gln 1 5 10 15gcc agc ctc cag ctc ata ggg tca ggc cat cag tgt gga gcc agc ctc 96 AlaSer Leu Gln Leu Ile Gly Ser Gly His Gln Cys Gly Ala Ser Leu 20 25 30 atcagt aac aca tgg ctg ctc aca gca gct cac tgc ttt tgg aaa aat 144 Ile SerAsn Thr Trp Leu Leu Thr Ala Ala His Cys Phe Trp Lys Asn 35 40 45 aaa gaccca act caa tgg att gct act ttt ggt gca act ata aca cca 192 Lys Asp ProThr Gln Trp Ile Ala Thr Phe Gly Ala Thr Ile Thr Pro 50 55 60 ccc gca gtgaaa cga aat gtg agg aaa att att ctt cat gag aat tac 240 Pro Ala Val LysArg Asn Val Arg Lys Ile Ile Leu His Glu Asn Tyr 65 70 75 80 cat aga gaaaca aat gaa aat gac att gct ttg gtt cag ctc tct act 288 His Arg Glu ThrAsn Glu Asn Asp Ile Ala Leu Val Gln Leu Ser Thr 85 90 95 gga gtt gag ttttca aat ata gtc cag aga gtt tgc ctc cca gac tca 336 Gly Val Glu Phe SerAsn Ile Val Gln Arg Val Cys Leu Pro Asp Ser 100 105 110 tct ata aag ttgcca cct aaa aca agt gtg ttc gtc aca gga ttt gga 384 Ser Ile Lys Leu ProPro Lys Thr Ser Val Phe Val Thr Gly Phe Gly 115 120 125 tcc att gta gatgat gga cct ata caa aat aca ctt cgg caa gcc aga 432 Ser Ile Val Asp AspGly Pro Ile Gln Asn Thr Leu Arg Gln Ala Arg 130 135 140 gtg gaa acc ataagc act gat gtg tgt aac aga aag gat gtg tat gat 480 Val Glu Thr Ile SerThr Asp Val Cys Asn Arg Lys Asp Val Tyr Asp 145 150 155 160 ggc ctg ataact cca gga atg tta tgt gct gga ttc atg gaa gga aaa 528 Gly Leu Ile ThrPro Gly Met Leu Cys Ala Gly Phe Met Glu Gly Lys 165 170 175 ata gat gcatgt aag gga gat tct ggt gga cct ctg gtt tat gat aat 576 Ile Asp Ala CysLys Gly Asp Ser Gly Gly Pro Leu Val Tyr Asp Asn 180 185 190 cat gac atctgg tac att gta ggt ata gta agt tgg gga caa tca tgt 624 His Asp Ile TrpTyr Ile Val Gly Ile Val Ser Trp Gly Gln Ser Cys 195 200 205 gca ctt cccaaa aaa cct gga gtc tac acc aga gta act aag tat cga 672 Ala Leu Pro LysLys Pro Gly Val Tyr Thr Arg Val Thr Lys Tyr Arg 210 215 220 gat tgg attgcc tca aag act ggt atg tag 702 Asp Trp Ile Ala Ser Lys Thr Gly Met *225 230 <210> SEQ ID NO 16 <211> LENGTH: 233 <212> TYPE: PRT <213>ORGANISM: Homo sapien <400> SEQUENCE: 16 Ile Val Gln Gly Arg Glu Thr AlaMet Glu Gly Glu Trp Pro Trp Gln 1 5 10 15 Ala Ser Leu Gln Leu Ile GlySer Gly His Gln Cys Gly Ala Ser Leu 20 25 30 Ile Ser Asn Thr Trp Leu LeuThr Ala Ala His Cys Phe Trp Lys Asn 35 40 45 Lys Asp Pro Thr Gln Trp IleAla Thr Phe Gly Ala Thr Ile Thr Pro 50 55 60 Pro Ala Val Lys Arg Asn ValArg Lys Ile Ile Leu His Glu Asn Tyr 65 70 75 80 His Arg Glu Thr Asn GluAsn Asp Ile Ala Leu Val Gln Leu Ser Thr 85 90 95 Gly Val Glu Phe Ser AsnIle Val Gln Arg Val Cys Leu Pro Asp Ser 100 105 110 Ser Ile Lys Leu ProPro Lys Thr Ser Val Phe Val Thr Gly Phe Gly 115 120 125 Ser Ile Val AspAsp Gly Pro Ile Gln Asn Thr Leu Arg Gln Ala Arg 130 135 140 Val Glu ThrIle Ser Thr Asp Val Cys Asn Arg Lys Asp Val Tyr Asp 145 150 155 160 GlyLeu Ile Thr Pro Gly Met Leu Cys Ala Gly Phe Met Glu Gly Lys 165 170 175Ile Asp Ala Cys Lys Gly Asp Ser Gly Gly Pro Leu Val Tyr Asp Asn 180 185190 His Asp Ile Trp Tyr Ile Val Gly Ile Val Ser Trp Gly Gln Ser Cys 195200 205 Ala Leu Pro Lys Lys Pro Gly Val Tyr Thr Arg Val Thr Lys Tyr Arg210 215 220 Asp Trp Ile Ala Ser Lys Thr Gly Met 225 230 <210> SEQ ID NO17 <211> LENGTH: 777 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (1)...(729) <223> OTHERINFORMATION: Nucleotide sequence encoding MTSP9, including proteasedomain (31-729) <400> SEQUENCE: 17 aaa cga gtt gtt cca tta aac gtc aacaga ata gca tct gga gtc att 48 Lys Arg Val Val Pro Leu Asn Val Asn ArgIle Ala Ser Gly Val Ile 1 5 10 15 gca ccc aag gcg gcc tgg cct tgg caagct tcc ctt cag tat gat aac 96 Ala Pro Lys Ala Ala Trp Pro Trp Gln AlaSer Leu Gln Tyr Asp Asn 20 25 30 atc cat cag tgt ggg gcc acc ttg att agtaac aca tgg ctt gtc act 144 Ile His Gln Cys Gly Ala Thr Leu Ile Ser AsnThr Trp Leu Val Thr 35 40 45 gca gca cac tgc ttc cag aag tat aaa aat ccacat caa tgg act gtt 192 Ala Ala His Cys Phe Gln Lys Tyr Lys Asn Pro HisGln Trp Thr Val 50 55 60 agt ttt gga aca aaa atc aac cct ccc tta atg aaaaga aat gtc aga 240 Ser Phe Gly Thr Lys Ile Asn Pro Pro Leu Met Lys ArgAsn Val Arg 65 70 75 80 aga ttt att atc cat gag aag tac cgc tct gca gcaaga gag tac gac 288 Arg Phe Ile Ile His Glu Lys Tyr Arg Ser Ala Ala ArgGlu Tyr Asp 85 90 95 att gct gtt gtg cag gtc tct tcc aga gtc acc ttt tcggat gac ata 336 Ile Ala Val Val Gln Val Ser Ser Arg Val Thr Phe Ser AspAsp Ile 100 105 110 cgc cgg att tgt ttg cca gaa gcc tct gca tcc ttc caacca aat ttg 384 Arg Arg Ile Cys Leu Pro Glu Ala Ser Ala Ser Phe Gln ProAsn Leu 115 120 125 act gtc cac atc aca gga ttt gga gca ctt tac tat ggtggg gaa tcc 432 Thr Val His Ile Thr Gly Phe Gly Ala Leu Tyr Tyr Gly GlyGlu Ser 130 135 140 caa aat gat ctc cga gaa gcc aga gtg aaa atc ata agtgac gat gtc 480 Gln Asn Asp Leu Arg Glu Ala Arg Val Lys Ile Ile Ser AspAsp Val 145 150 155 160 tgc aag caa cca cag gtg tat ggc aat gat ata aaacct gga atg ttc 528 Cys Lys Gln Pro Gln Val Tyr Gly Asn Asp Ile Lys ProGly Met Phe 165 170 175 tgt gcc gga tat atg gaa gga att tat gat gcc tgcagg ggt gat tct 576 Cys Ala Gly Tyr Met Glu Gly Ile Tyr Asp Ala Cys ArgGly Asp Ser 180 185 190 ggg gga cct tta gtc aca agg gat ctg aaa gat acgtgg tat ctc att 624 Gly Gly Pro Leu Val Thr Arg Asp Leu Lys Asp Thr TrpTyr Leu Ile 195 200 205 gga att gta agc tgg gga gat aac tgt ggt caa aaggac aag cct gga 672 Gly Ile Val Ser Trp Gly Asp Asn Cys Gly Gln Lys AspLys Pro Gly 210 215 220 gtc tac aca caa gtg act tat tac cga aac tgg attgct tca aaa aca 720 Val Tyr Thr Gln Val Thr Tyr Tyr Arg Asn Trp Ile AlaSer Lys Thr 225 230 235 240 ggc atc taa ttcacgataa aagttaaaca aagaaagctgtatgcaggtc atatatgc 777 Gly Ile <210> SEQ ID NO 18 <211> LENGTH: 242<212> TYPE: PRT <213> ORGANISM: Homo Sapien <220> FEATURE: <221>NAME/KEY: SITE <222> LOCATION: (11)...(242) <223> OTHER INFORMATION:MTSP9 protease domain <400> SEQUENCE: 18 Lys Arg Val Val Pro Leu Asn ValAsn Arg Ile Ala Ser Gly Val Ile 1 5 10 15 Ala Pro Lys Ala Ala Trp ProTrp Gln Ala Ser Leu Gln Tyr Asp Asn 20 25 30 Ile His Gln Cys Gly Ala ThrLeu Ile Ser Asn Thr Trp Leu Val Thr 35 40 45 Ala Ala His Cys Phe Gln LysTyr Lys Asn Pro His Gln Trp Thr Val 50 55 60 Ser Phe Gly Thr Lys Ile AsnPro Pro Leu Met Lys Arg Asn Val Arg 65 70 75 80 Arg Phe Ile Ile His GluLys Tyr Arg Ser Ala Ala Arg Glu Tyr Asp 85 90 95 Ile Ala Val Val Gln ValSer Ser Arg Val Thr Phe Ser Asp Asp Ile 100 105 110 Arg Arg Ile Cys LeuPro Glu Ala Ser Ala Ser Phe Gln Pro Asn Leu 115 120 125 Thr Val His IleThr Gly Phe Gly Ala Leu Tyr Tyr Gly Gly Glu Ser 130 135 140 Gln Asn AspLeu Arg Glu Ala Arg Val Lys Ile Ile Ser Asp Asp Val 145 150 155 160 CysLys Gln Pro Gln Val Tyr Gly Asn Asp Ile Lys Pro Gly Met Phe 165 170 175Cys Ala Gly Tyr Met Glu Gly Ile Tyr Asp Ala Cys Arg Gly Asp Ser 180 185190 Gly Gly Pro Leu Val Thr Arg Asp Leu Lys Asp Thr Trp Tyr Leu Ile 195200 205 Gly Ile Val Ser Trp Gly Asp Asn Cys Gly Gln Lys Asp Lys Pro Gly210 215 220 Val Tyr Thr Gln Val Thr Tyr Tyr Arg Asn Trp Ile Ala Ser LysThr 225 230 235 240 Gly Ile <210> SEQ ID NO 19 <211> LENGTH: 3316 <212>TYPE: DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (1)...(3282) <223> OTHER INFORMATION: Nucleotidesequence encoding MTSP12, including MTSP12-PD1, MTSP12-PD2, andMTSP12-PD3 protease domains <400> SEQUENCE: 19 atg gag ccc act gtg gctaac gta cac ctc gtg ccc agg aca acc aag 48 Met Glu Pro Thr Val Ala AsnVal His Leu Val Pro Arg Thr Thr Lys 1 5 10 15 gaa gtc ccc gct ctg gatgcc gcg tgc tgt cga gcg gcc acc att ggc 96 Glu Val Pro Ala Leu Asp AlaAla Cys Cys Arg Ala Ala Thr Ile Gly 20 25 30 gtg gtg gcc acc agc ctt gtcgtc ctc acc ctg gga gtc ctt ttg gcc 144 Val Val Ala Thr Ser Leu Val ValLeu Thr Leu Gly Val Leu Leu Ala 35 40 45 ttc ctc tct aca cag ggc ttc cacgtg gac cac acg gcc gag ctg cgg 192 Phe Leu Ser Thr Gln Gly Phe His ValAsp His Thr Ala Glu Leu Arg 50 55 60 gga atc cgg tgg acc agc agt ttg cggcgg gag acc tcg gac tat cac 240 Gly Ile Arg Trp Thr Ser Ser Leu Arg ArgGlu Thr Ser Asp Tyr His 65 70 75 80 cgc acg ctg acg ccc acc ctg gag gcactg ttt gta agt agt ttt cag 288 Arg Thr Leu Thr Pro Thr Leu Glu Ala LeuPhe Val Ser Ser Phe Gln 85 90 95 aag aca gag tta gag gca agc tgc gtg ggttgc tcg gta ctg aat tat 336 Lys Thr Glu Leu Glu Ala Ser Cys Val Gly CysSer Val Leu Asn Tyr 100 105 110 agg gat ggg aac tcc agt gtc ctc gta catttc cag ctg cac ttt ctg 384 Arg Asp Gly Asn Ser Ser Val Leu Val His PheGln Leu His Phe Leu 115 120 125 ctg cga ccc ctc cag acg ctg agc ctg ggcctg gag gag gag cta ttg 432 Leu Arg Pro Leu Gln Thr Leu Ser Leu Gly LeuGlu Glu Glu Leu Leu 130 135 140 cag cga ggg atc cgg gca agg ctg cgg gagcac ggc atc tcc ctg gct 480 Gln Arg Gly Ile Arg Ala Arg Leu Arg Glu HisGly Ile Ser Leu Ala 145 150 155 160 gcc tat ggc aca att gtg tcg gct gagctc aca ggg aga cat aag ggg 528 Ala Tyr Gly Thr Ile Val Ser Ala Glu LeuThr Gly Arg His Lys Gly 165 170 175 ccc ttg gca gaa aga gac ttc aaa tcaggc cgc tgt cca ggg aac tcc 576 Pro Leu Ala Glu Arg Asp Phe Lys Ser GlyArg Cys Pro Gly Asn Ser 180 185 190 ttt tcc tgc ggg aac agc cag tgt gtgacc aag gtg aac ccg gag tgt 624 Phe Ser Cys Gly Asn Ser Gln Cys Val ThrLys Val Asn Pro Glu Cys 195 200 205 gac gac cag gag gac tgc tcc gat gggtcc gac gag gcg cac tgc gag 672 Asp Asp Gln Glu Asp Cys Ser Asp Gly SerAsp Glu Ala His Cys Glu 210 215 220 tgt ggc ttg cag cct gcc tgg agg atggcc ggc agg atc gtg ggc ggc 720 Cys Gly Leu Gln Pro Ala Trp Arg Met AlaGly Arg Ile Val Gly Gly 225 230 235 240 atg gaa gca tcc ccg ggg gag tttccg tgg caa gcc agc ctt cga gag 768 Met Glu Ala Ser Pro Gly Glu Phe ProTrp Gln Ala Ser Leu Arg Glu 245 250 255 aac aag gag cac ttc tgt ggg gccgcc atc atc aac gcc agg tgg ctg 816 Asn Lys Glu His Phe Cys Gly Ala AlaIle Ile Asn Ala Arg Trp Leu 260 265 270 gtg tct gct gct cac tgc ttc aatgag ttc caa gac ccg acg aag tgg 864 Val Ser Ala Ala His Cys Phe Asn GluPhe Gln Asp Pro Thr Lys Trp 275 280 285 gtg gcc tac gtg ggt gcg acc tacctc agc ggc tcg gag gcc agc acc 912 Val Ala Tyr Val Gly Ala Thr Tyr LeuSer Gly Ser Glu Ala Ser Thr 290 295 300 gtg cgg gcc cag gtg gtc cag atcgtc aag cac ccc ctg tac aac gcg 960 Val Arg Ala Gln Val Val Gln Ile ValLys His Pro Leu Tyr Asn Ala 305 310 315 320 gac acg gcc gac ttt gac gtggct gtg ctg gag ctg acc agc cct ctg 1008 Asp Thr Ala Asp Phe Asp Val AlaVal Leu Glu Leu Thr Ser Pro Leu 325 330 335 cct ttc ggc cgg cac atc cagccc gtg tgc ctc ccg gct gcc aca cac 1056 Pro Phe Gly Arg His Ile Gln ProVal Cys Leu Pro Ala Ala Thr His 340 345 350 atc ttc cca ccc agc aag aagtgc ctg atc tca ggc tgg ggc tac ctc 1104 Ile Phe Pro Pro Ser Lys Lys CysLeu Ile Ser Gly Trp Gly Tyr Leu 355 360 365 aag gag gac ttc ctg gtc aagcca ggg gtg ctg cag aaa gcc act gtg 1152 Lys Glu Asp Phe Leu Val Lys ProGly Val Leu Gln Lys Ala Thr Val 370 375 380 gag ctg ctg gac cag gca ctgtgt gcc agc ttg tac ggc cat tca ctc 1200 Glu Leu Leu Asp Gln Ala Leu CysAla Ser Leu Tyr Gly His Ser Leu 385 390 395 400 act gac agg atg gtg tgcgct ggc tac ctg gac ggg aag gtg gac tcc 1248 Thr Asp Arg Met Val Cys AlaGly Tyr Leu Asp Gly Lys Val Asp Ser 405 410 415 tgc cag ggt gac tca ggagga ccc ctg gtc tgc gag gag ccc tct ggc 1296 Cys Gln Gly Asp Ser Gly GlyPro Leu Val Cys Glu Glu Pro Ser Gly 420 425 430 cgg ttc tct ctg gct ggcatc gtg agc tgg gga atc ggg tgt gcg gaa 1344 Arg Phe Ser Leu Ala Gly IleVal Ser Trp Gly Ile Gly Cys Ala Glu 435 440 445 gcc cgg cgt cca ggg gtctat gcc cga gtc acc agg cta cgt gac tgg 1392 Ala Arg Arg Pro Gly Val TyrAla Arg Val Thr Arg Leu Arg Asp Trp 450 455 460 atc ctg gag gcc acc accaaa gcc agc atg cct ctg gcc ccc acc atg 1440 Ile Leu Glu Ala Thr Thr LysAla Ser Met Pro Leu Ala Pro Thr Met 465 470 475 480 gct cct gcc cct gccgcc ccc agc aca gcc tgg ccc acc agt cct gag 1488 Ala Pro Ala Pro Ala AlaPro Ser Thr Ala Trp Pro Thr Ser Pro Glu 485 490 495 agc cct gtt gtc agcacc ccc acc aaa tcg atg cag gcc ctc agt acc 1536 Ser Pro Val Val Ser ThrPro Thr Lys Ser Met Gln Ala Leu Ser Thr 500 505 510 gtg cct ctt gac tgggtc acc gtt cct aag cta caa gaa tgt ggg gcc 1584 Val Pro Leu Asp Trp ValThr Val Pro Lys Leu Gln Glu Cys Gly Ala 515 520 525 agg cct gca atg gagaag ccc acc cgg gtc gtg ggc ggg ttc gga gct 1632 Arg Pro Ala Met Glu LysPro Thr Arg Val Val Gly Gly Phe Gly Ala 530 535 540 gcc tcc ggg gag gtgccc tgg cag gtc agc ctg aag gaa ggg tcc cgg 1680 Ala Ser Gly Glu Val ProTrp Gln Val Ser Leu Lys Glu Gly Ser Arg 545 550 555 560 cac ttc tgc ggagca act gtg gtg ggg gac cgc tgg ctg ctg tct gcc 1728 His Phe Cys Gly AlaThr Val Val Gly Asp Arg Trp Leu Leu Ser Ala 565 570 575 gcc cac tgc ttcaac cac acg aag gtg gag cag gtt cgg gcc cac ctg 1776 Ala His Cys Phe AsnHis Thr Lys Val Glu Gln Val Arg Ala His Leu 580 585 590 ggc act gcg tccctc ctg ggc ctg ggc ggg agc ccg gtg aag atc ggg 1824 Gly Thr Ala Ser LeuLeu Gly Leu Gly Gly Ser Pro Val Lys Ile Gly 595 600 605 ctg cgg cgg gtagtg ctg cac ccc ctc tac aac cct ggc atc ctg gac 1872 Leu Arg Arg Val ValLeu His Pro Leu Tyr Asn Pro Gly Ile Leu Asp 610 615 620 ttc gac ctg gctgtc ctg gag ctg gcc agc ccc ctg gcc ttc aac aaa 1920 Phe Asp Leu Ala ValLeu Glu Leu Ala Ser Pro Leu Ala Phe Asn Lys 625 630 635 640 tac atc cagcct gtc tgc ctg ccc ctg gcc atc cgg aag ttc cct gtg 1968 Tyr Ile Gln ProVal Cys Leu Pro Leu Ala Ile Arg Lys Phe Pro Val 645 650 655 ggc cgg aagtgc atg atc tcc gga tgg gga aat acg cag gaa gga aat 2016 Gly Arg Lys CysMet Ile Ser Gly Trp Gly Asn Thr Gln Glu Gly Asn 660 665 670 gcc acc aagccc gag ctc ctg cag aag gcg tcc gtg ggc atc ata gac 2064 Ala Thr Lys ProGlu Leu Leu Gln Lys Ala Ser Val Gly Ile Ile Asp 675 680 685 cag aaa acctgt agt gtg ctc tac aac ttc tcc ctc aca gac cgc atg 2112 Gln Lys Thr CysSer Val Leu Tyr Asn Phe Ser Leu Thr Asp Arg Met 690 695 700 atc tgc gcaggc ttc ctg gaa ggc aaa gtc gac tcc tgc cag ggt gac 2160 Ile Cys Ala GlyPhe Leu Glu Gly Lys Val Asp Ser Cys Gln Gly Asp 705 710 715 720 tct gggggc ccc ctg gcc tgc gag gag gcc cct ggc gtg ttt tat ctg 2208 Ser Gly GlyPro Leu Ala Cys Glu Glu Ala Pro Gly Val Phe Tyr Leu 725 730 735 gca gggatc gtg agc tgg ggt att ggc tgc gct cag gtt aag aag ccg 2256 Ala Gly IleVal Ser Trp Gly Ile Gly Cys Ala Gln Val Lys Lys Pro 740 745 750 ggc gtgtac acg cgc atc acc agg cta aag ggc tgg atc ctg gag atc 2304 Gly Val TyrThr Arg Ile Thr Arg Leu Lys Gly Trp Ile Leu Glu Ile 755 760 765 atg tcctcc cag ccc ctt ccc atg tct ccc ccc tcg acc aca agg atg 2352 Met Ser SerGln Pro Leu Pro Met Ser Pro Pro Ser Thr Thr Arg Met 770 775 780 ctg gccacc acc agc ccc agg acg aca gct ggc ctc aca gtc ccg ggg 2400 Leu Ala ThrThr Ser Pro Arg Thr Thr Ala Gly Leu Thr Val Pro Gly 785 790 795 800 gccaca ccc agc aga ccc acc cct ggg gct gcc agc agg gtg acg ggc 2448 Ala ThrPro Ser Arg Pro Thr Pro Gly Ala Ala Ser Arg Val Thr Gly 805 810 815 caacct gcc aac tca acc tta tct gcc gtg agc acc act gct agg gga 2496 Gln ProAla Asn Ser Thr Leu Ser Ala Val Ser Thr Thr Ala Arg Gly 820 825 830 cagacg cca ttt cca gac gcc ccg gag gcc acc aca cac acc cag cta 2544 Gln ThrPro Phe Pro Asp Ala Pro Glu Ala Thr Thr His Thr Gln Leu 835 840 845 ccagac tgt ggc ctg gcg ccg gcc gcg ctc acc agg att gtg ggc ggc 2592 Pro AspCys Gly Leu Ala Pro Ala Ala Leu Thr Arg Ile Val Gly Gly 850 855 860 agcgca gcg ggc cgt ggg gag tgg ccg tgg cag gtg ggc ctg tgg ctg 2640 Ser AlaAla Gly Arg Gly Glu Trp Pro Trp Gln Val Gly Leu Trp Leu 865 870 875 880cgg cgc cgg gaa cac cgt tgc ggg gcc gtg ctg gtg gca gag agg tgg 2688 ArgArg Arg Glu His Arg Cys Gly Ala Val Leu Val Ala Glu Arg Trp 885 890 895ctg ctg tcg gcg gcg cac tgc ttc gac gtc tac ggg gac ccc aag cag 2736 LeuLeu Ser Ala Ala His Cys Phe Asp Val Tyr Gly Asp Pro Lys Gln 900 905 910tgg gcg gcc ttc cta ggc acg ccg ttc ctg agc ggc gcg gag ggg cag 2784 TrpAla Ala Phe Leu Gly Thr Pro Phe Leu Ser Gly Ala Glu Gly Gln 915 920 925ctg gag cgc gtg gcg cgc atc tac aag cac ccg ttc tac aat ctc tac 2832 LeuGlu Arg Val Ala Arg Ile Tyr Lys His Pro Phe Tyr Asn Leu Tyr 930 935 940acg ctc gac tac gac gtg gcg ctt ctg gag ctg gcg ggg ccg gtg cgt 2880 ThrLeu Asp Tyr Asp Val Ala Leu Leu Glu Leu Ala Gly Pro Val Arg 945 950 955960 cgc agc cgc ctg gtg cgt ccc atc tgc ctg ccc gag ccc gcg ccg cga 2928Arg Ser Arg Leu Val Arg Pro Ile Cys Leu Pro Glu Pro Ala Pro Arg 965 970975 ccc ccg gac ggc acg cgc tgc gtc atc acc ggc tgg ggc tcg gtg cgc 2976Pro Pro Asp Gly Thr Arg Cys Val Ile Thr Gly Trp Gly Ser Val Arg 980 985990 gaa gga ggc tcc atg gcg cgg cag ctg cag aag gcg gcc gtg cgc ctc 3024Glu Gly Gly Ser Met Ala Arg Gln Leu Gln Lys Ala Ala Val Arg Leu 995 10001005 ctc agc gag cag acc tgc cgc cgc ttc tac cca gtg cag atc agc agc3072 Leu Ser Glu Gln Thr Cys Arg Arg Phe Tyr Pro Val Gln Ile Ser Ser1010 1015 1020 cgc atg ctg tgt gcc ggc ttc ccg cag ggt ggc gtg gac agctgc tcg 3120 Arg Met Leu Cys Ala Gly Phe Pro Gln Gly Gly Val Asp Ser CysSer 1025 1030 1035 1040 ggt gac gct ggg gga ccc ctg gcc tgc agg gag ccctct gga cgg tgg 3168 Gly Asp Ala Gly Gly Pro Leu Ala Cys Arg Glu Pro SerGly Arg Trp 1045 1050 1055 gtg cta act ggg gtc act agc tgg ggc tat ggctgt ggc cgg ccc cac 3216 Val Leu Thr Gly Val Thr Ser Trp Gly Tyr Gly CysGly Arg Pro His 1060 1065 1070 ttc cca ggt gtc tat acc cgg gtg gca gctgtg aga ggc tgg ata gga 3264 Phe Pro Gly Val Tyr Thr Arg Val Ala Ala ValArg Gly Trp Ile Gly 1075 1080 1085 cag cac atc cag gag tga ccaccacgtgactgcccagg ccgagactct 3312 Gln His Ile Gln Glu * 1090 acgt 3316 <210>SEQ ID NO 20 <211> LENGTH: 1093 <212> TYPE: PRT <213> ORGANISM: HomoSapien <400> SEQUENCE: 20 Met Glu Pro Thr Val Ala Asn Val His Leu ValPro Arg Thr Thr Lys 1 5 10 15 Glu Val Pro Ala Leu Asp Ala Ala Cys CysArg Ala Ala Thr Ile Gly 20 25 30 Val Val Ala Thr Ser Leu Val Val Leu ThrLeu Gly Val Leu Leu Ala 35 40 45 Phe Leu Ser Thr Gln Gly Phe His Val AspHis Thr Ala Glu Leu Arg 50 55 60 Gly Ile Arg Trp Thr Ser Ser Leu Arg ArgGlu Thr Ser Asp Tyr His 65 70 75 80 Arg Thr Leu Thr Pro Thr Leu Glu AlaLeu Phe Val Ser Ser Phe Gln 85 90 95 Lys Thr Glu Leu Glu Ala Ser Cys ValGly Cys Ser Val Leu Asn Tyr 100 105 110 Arg Asp Gly Asn Ser Ser Val LeuVal His Phe Gln Leu His Phe Leu 115 120 125 Leu Arg Pro Leu Gln Thr LeuSer Leu Gly Leu Glu Glu Glu Leu Leu 130 135 140 Gln Arg Gly Ile Arg AlaArg Leu Arg Glu His Gly Ile Ser Leu Ala 145 150 155 160 Ala Tyr Gly ThrIle Val Ser Ala Glu Leu Thr Gly Arg His Lys Gly 165 170 175 Pro Leu AlaGlu Arg Asp Phe Lys Ser Gly Arg Cys Pro Gly Asn Ser 180 185 190 Phe SerCys Gly Asn Ser Gln Cys Val Thr Lys Val Asn Pro Glu Cys 195 200 205 AspAsp Gln Glu Asp Cys Ser Asp Gly Ser Asp Glu Ala His Cys Glu 210 215 220Cys Gly Leu Gln Pro Ala Trp Arg Met Ala Gly Arg Ile Val Gly Gly 225 230235 240 Met Glu Ala Ser Pro Gly Glu Phe Pro Trp Gln Ala Ser Leu Arg Glu245 250 255 Asn Lys Glu His Phe Cys Gly Ala Ala Ile Ile Asn Ala Arg TrpLeu 260 265 270 Val Ser Ala Ala His Cys Phe Asn Glu Phe Gln Asp Pro ThrLys Trp 275 280 285 Val Ala Tyr Val Gly Ala Thr Tyr Leu Ser Gly Ser GluAla Ser Thr 290 295 300 Val Arg Ala Gln Val Val Gln Ile Val Lys His ProLeu Tyr Asn Ala 305 310 315 320 Asp Thr Ala Asp Phe Asp Val Ala Val LeuGlu Leu Thr Ser Pro Leu 325 330 335 Pro Phe Gly Arg His Ile Gln Pro ValCys Leu Pro Ala Ala Thr His 340 345 350 Ile Phe Pro Pro Ser Lys Lys CysLeu Ile Ser Gly Trp Gly Tyr Leu 355 360 365 Lys Glu Asp Phe Leu Val LysPro Gly Val Leu Gln Lys Ala Thr Val 370 375 380 Glu Leu Leu Asp Gln AlaLeu Cys Ala Ser Leu Tyr Gly His Ser Leu 385 390 395 400 Thr Asp Arg MetVal Cys Ala Gly Tyr Leu Asp Gly Lys Val Asp Ser 405 410 415 Cys Gln GlyAsp Ser Gly Gly Pro Leu Val Cys Glu Glu Pro Ser Gly 420 425 430 Arg PheSer Leu Ala Gly Ile Val Ser Trp Gly Ile Gly Cys Ala Glu 435 440 445 AlaArg Arg Pro Gly Val Tyr Ala Arg Val Thr Arg Leu Arg Asp Trp 450 455 460Ile Leu Glu Ala Thr Thr Lys Ala Ser Met Pro Leu Ala Pro Thr Met 465 470475 480 Ala Pro Ala Pro Ala Ala Pro Ser Thr Ala Trp Pro Thr Ser Pro Glu485 490 495 Ser Pro Val Val Ser Thr Pro Thr Lys Ser Met Gln Ala Leu SerThr 500 505 510 Val Pro Leu Asp Trp Val Thr Val Pro Lys Leu Gln Glu CysGly Ala 515 520 525 Arg Pro Ala Met Glu Lys Pro Thr Arg Val Val Gly GlyPhe Gly Ala 530 535 540 Ala Ser Gly Glu Val Pro Trp Gln Val Ser Leu LysGlu Gly Ser Arg 545 550 555 560 His Phe Cys Gly Ala Thr Val Val Gly AspArg Trp Leu Leu Ser Ala 565 570 575 Ala His Cys Phe Asn His Thr Lys ValGlu Gln Val Arg Ala His Leu 580 585 590 Gly Thr Ala Ser Leu Leu Gly LeuGly Gly Ser Pro Val Lys Ile Gly 595 600 605 Leu Arg Arg Val Val Leu HisPro Leu Tyr Asn Pro Gly Ile Leu Asp 610 615 620 Phe Asp Leu Ala Val LeuGlu Leu Ala Ser Pro Leu Ala Phe Asn Lys 625 630 635 640 Tyr Ile Gln ProVal Cys Leu Pro Leu Ala Ile Arg Lys Phe Pro Val 645 650 655 Gly Arg LysCys Met Ile Ser Gly Trp Gly Asn Thr Gln Glu Gly Asn 660 665 670 Ala ThrLys Pro Glu Leu Leu Gln Lys Ala Ser Val Gly Ile Ile Asp 675 680 685 GlnLys Thr Cys Ser Val Leu Tyr Asn Phe Ser Leu Thr Asp Arg Met 690 695 700Ile Cys Ala Gly Phe Leu Glu Gly Lys Val Asp Ser Cys Gln Gly Asp 705 710715 720 Ser Gly Gly Pro Leu Ala Cys Glu Glu Ala Pro Gly Val Phe Tyr Leu725 730 735 Ala Gly Ile Val Ser Trp Gly Ile Gly Cys Ala Gln Val Lys LysPro 740 745 750 Gly Val Tyr Thr Arg Ile Thr Arg Leu Lys Gly Trp Ile LeuGlu Ile 755 760 765 Met Ser Ser Gln Pro Leu Pro Met Ser Pro Pro Ser ThrThr Arg Met 770 775 780 Leu Ala Thr Thr Ser Pro Arg Thr Thr Ala Gly LeuThr Val Pro Gly 785 790 795 800 Ala Thr Pro Ser Arg Pro Thr Pro Gly AlaAla Ser Arg Val Thr Gly 805 810 815 Gln Pro Ala Asn Ser Thr Leu Ser AlaVal Ser Thr Thr Ala Arg Gly 820 825 830 Gln Thr Pro Phe Pro Asp Ala ProGlu Ala Thr Thr His Thr Gln Leu 835 840 845 Pro Asp Cys Gly Leu Ala ProAla Ala Leu Thr Arg Ile Val Gly Gly 850 855 860 Ser Ala Ala Gly Arg GlyGlu Trp Pro Trp Gln Val Gly Leu Trp Leu 865 870 875 880 Arg Arg Arg GluHis Arg Cys Gly Ala Val Leu Val Ala Glu Arg Trp 885 890 895 Leu Leu SerAla Ala His Cys Phe Asp Val Tyr Gly Asp Pro Lys Gln 900 905 910 Trp AlaAla Phe Leu Gly Thr Pro Phe Leu Ser Gly Ala Glu Gly Gln 915 920 925 LeuGlu Arg Val Ala Arg Ile Tyr Lys His Pro Phe Tyr Asn Leu Tyr 930 935 940Thr Leu Asp Tyr Asp Val Ala Leu Leu Glu Leu Ala Gly Pro Val Arg 945 950955 960 Arg Ser Arg Leu Val Arg Pro Ile Cys Leu Pro Glu Pro Ala Pro Arg965 970 975 Pro Pro Asp Gly Thr Arg Cys Val Ile Thr Gly Trp Gly Ser ValArg 980 985 990 Glu Gly Gly Ser Met Ala Arg Gln Leu Gln Lys Ala Ala ValArg Leu 995 1000 1005 Leu Ser Glu Gln Thr Cys Arg Arg Phe Tyr Pro ValGln Ile Ser Ser 1010 1015 1020 Arg Met Leu Cys Ala Gly Phe Pro Gln GlyGly Val Asp Ser Cys Ser 1025 1030 1035 1040 Gly Asp Ala Gly Gly Pro LeuAla Cys Arg Glu Pro Ser Gly Arg Trp 1045 1050 1055 Val Leu Thr Gly ValThr Ser Trp Gly Tyr Gly Cys Gly Arg Pro His 1060 1065 1070 Phe Pro GlyVal Tyr Thr Arg Val Ala Ala Val Arg Gly Trp Ile Gly 1075 1080 1085 GlnHis Ile Gln Glu 1090 <210> SEQ ID NO 21 <211> LENGTH: 702 <212> TYPE:DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (1)...(699) <223> OTHER INFORMATION: Nucleic Acid encodingprotease domain of endotheliase 1 <400> SEQUENCE: 21 agg atc gtt ggt gggaca gaa gta gaa gag ggt gaa tgg ccc tgg cag 48 Arg Ile Val Gly Gly ThrGlu Val Glu Glu Gly Glu Trp Pro Trp Gln 1 5 10 15 gct agc ctg cag tgggat ggg agt cat cgc tgt gga gca acc tta att 96 Ala Ser Leu Gln Trp AspGly Ser His Arg Cys Gly Ala Thr Leu Ile 20 25 30 aat gcc aca tgg ctt gtgagt gct gct cac tgt ttt aca aca tat aag 144 Asn Ala Thr Trp Leu Val SerAla Ala His Cys Phe Thr Thr Tyr Lys 35 40 45 aac cct gcc aga tgg act gcttcc ttt gga gta aca ata aaa cct tcg 192 Asn Pro Ala Arg Trp Thr Ala SerPhe Gly Val Thr Ile Lys Pro Ser 50 55 60 aaa atg aaa cgg ggt ctc cgg agaata att gtc cat gaa aaa tac aaa 240 Lys Met Lys Arg Gly Leu Arg Arg IleIle Val His Glu Lys Tyr Lys 65 70 75 80 cac cca tca cat gac tat gat atttct ctt gca gag ctt tct agc cct 288 His Pro Ser His Asp Tyr Asp Ile SerLeu Ala Glu Leu Ser Ser Pro 85 90 95 gtt ccc tac aca aat gca gta cat agagtt tgt ctc cct gat gca tcc 336 Val Pro Tyr Thr Asn Ala Val His Arg ValCys Leu Pro Asp Ala Ser 100 105 110 tat gag ttt caa cca ggt gat gtg atgttt gtg aca gga ttt gga gca 384 Tyr Glu Phe Gln Pro Gly Asp Val Met PheVal Thr Gly Phe Gly Ala 115 120 125 ctg aaa aat gat ggt tac agt caa aatcat ctt cga caa gca cag gtg 432 Leu Lys Asn Asp Gly Tyr Ser Gln Asn HisLeu Arg Gln Ala Gln Val 130 135 140 act ctc ata gac gct aca act tgc aatgaa cct caa gct tac aat gac 480 Thr Leu Ile Asp Ala Thr Thr Cys Asn GluPro Gln Ala Tyr Asn Asp 145 150 155 160 gcc ata act cct aga atg tta tgtgct ggc tcc tta gaa gga aaa aca 528 Ala Ile Thr Pro Arg Met Leu Cys AlaGly Ser Leu Glu Gly Lys Thr 165 170 175 gat gca tgc cag ggt gac tct ggagga cca ctg gtt agt tca gat gct 576 Asp Ala Cys Gln Gly Asp Ser Gly GlyPro Leu Val Ser Ser Asp Ala 180 185 190 aga gat atc tgg tac ctt gct ggaata gtg agc tgg gga gat gaa tgt 624 Arg Asp Ile Trp Tyr Leu Ala Gly IleVal Ser Trp Gly Asp Glu Cys 195 200 205 gcg aaa ccc aac aag cct ggt gtttat act aga gtt acg gcc ttg cgg 672 Ala Lys Pro Asn Lys Pro Gly Val TyrThr Arg Val Thr Ala Leu Arg 210 215 220 gac tgg att act tca aaa act ggtatc taa 702 Asp Trp Ile Thr Ser Lys Thr Gly Ile 225 230 <210> SEQ ID NO22 <211> LENGTH: 233 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: SITE <222> LOCATION: (1)...(233) <223> OTHERINFORMATION: Protease domain of endotheliase 1 <400> SEQUENCE: 22 ArgIle Val Gly Gly Thr Glu Val Glu Glu Gly Glu Trp Pro Trp Gln 1 5 10 15Ala Ser Leu Gln Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu Ile 20 25 30Asn Ala Thr Trp Leu Val Ser Ala Ala His Cys Phe Thr Thr Tyr Lys 35 40 45Asn Pro Ala Arg Trp Thr Ala Ser Phe Gly Val Thr Ile Lys Pro Ser 50 55 60Lys Met Lys Arg Gly Leu Arg Arg Ile Ile Val His Glu Lys Tyr Lys 65 70 7580 His Pro Ser His Asp Tyr Asp Ile Ser Leu Ala Glu Leu Ser Ser Pro 85 9095 Val Pro Tyr Thr Asn Ala Val His Arg Val Cys Leu Pro Asp Ala Ser 100105 110 Tyr Glu Phe Gln Pro Gly Asp Val Met Phe Val Thr Gly Phe Gly Ala115 120 125 Leu Lys Asn Asp Gly Tyr Ser Gln Asn His Leu Arg Gln Ala GlnVal 130 135 140 Thr Leu Ile Asp Ala Thr Thr Cys Asn Glu Pro Gln Ala TyrAsn Asp 145 150 155 160 Ala Ile Thr Pro Arg Met Leu Cys Ala Gly Ser LeuGlu Gly Lys Thr 165 170 175 Asp Ala Cys Gln Gly Asp Ser Gly Gly Pro LeuVal Ser Ser Asp Ala 180 185 190 Arg Asp Ile Trp Tyr Leu Ala Gly Ile ValSer Trp Gly Asp Glu Cys 195 200 205 Ala Lys Pro Asn Lys Pro Gly Val TyrThr Arg Val Thr Ala Leu Arg 210 215 220 Asp Trp Ile Thr Ser Lys Thr GlyIle 225 230 <210> SEQ ID NO 23 <211> LENGTH: 1689 <212> TYPE: DNA <213>ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(1)...(1689) <223> OTHER INFORMATION: Nucleic acid encoding Endotheliase2-S protein <400> SEQUENCE: 23 atg gag agg gac agc cac ggg aat gca tctcca gca aga aca cct tca 48 Met Glu Arg Asp Ser His Gly Asn Ala Ser ProAla Arg Thr Pro Ser 1 5 10 15 gct gga gca tct cca gcc cag gca tct ccagct ggg aca cct cca ggc 96 Ala Gly Ala Ser Pro Ala Gln Ala Ser Pro AlaGly Thr Pro Pro Gly 20 25 30 cgg gca tct cca gcc cag gca tct cca gcc caggca tct cca gct ggg 144 Arg Ala Ser Pro Ala Gln Ala Ser Pro Ala Gln AlaSer Pro Ala Gly 35 40 45 aca cct ccg ggc cgg gca tct cca gcc cag gca tctcca gct ggt aca 192 Thr Pro Pro Gly Arg Ala Ser Pro Ala Gln Ala Ser ProAla Gly Thr 50 55 60 cct cca ggc cgg gca tct cca ggc cgg gca tct cca gcccag gca tct 240 Pro Pro Gly Arg Ala Ser Pro Gly Arg Ala Ser Pro Ala GlnAla Ser 65 70 75 80 cca gcc cgg gca tct ccg gct ctg gca tca ctt tcc aggtcc tca tcc 288 Pro Ala Arg Ala Ser Pro Ala Leu Ala Ser Leu Ser Arg SerSer Ser 85 90 95 ggc agg tca tca tcc gcc agg tca gcc tcg gtg aca acc tcccca acc 336 Gly Arg Ser Ser Ser Ala Arg Ser Ala Ser Val Thr Thr Ser ProThr 100 105 110 aga gtg tac ctt gtt aga gca aca cca gtg ggg gct gta cccatc cga 384 Arg Val Tyr Leu Val Arg Ala Thr Pro Val Gly Ala Val Pro IleArg 115 120 125 tca tct cct gcc agg tca gca cca gca acc agg gcc acc agggag agc 432 Ser Ser Pro Ala Arg Ser Ala Pro Ala Thr Arg Ala Thr Arg GluSer 130 135 140 cca ggt acg agc ctg ccc aag ttc acc tgg cgg gag ggc cagaag cag 480 Pro Gly Thr Ser Leu Pro Lys Phe Thr Trp Arg Glu Gly Gln LysGln 145 150 155 160 cta ccg ctc atc ggg tgc gtg ctc ctc ctc att gcc ctggtg gtt tcg 528 Leu Pro Leu Ile Gly Cys Val Leu Leu Leu Ile Ala Leu ValVal Ser 165 170 175 ctc atc atc ctc ttc cag ttc tgg cag ggc cac aca gggatc agg tac 576 Leu Ile Ile Leu Phe Gln Phe Trp Gln Gly His Thr Gly IleArg Tyr 180 185 190 aag gag cag agg gag agc tgt ccc aag cac gct gtt cgctgt gac ggg 624 Lys Glu Gln Arg Glu Ser Cys Pro Lys His Ala Val Arg CysAsp Gly 195 200 205 gtg gtg gac tgc aag ctg aag agt gac gag ctg ggc tgcgtg agg ttt 672 Val Val Asp Cys Lys Leu Lys Ser Asp Glu Leu Gly Cys ValArg Phe 210 215 220 gac tgg gac aag tct ctg ctt aaa atc tac tct ggg tcctcc cat cag 720 Asp Trp Asp Lys Ser Leu Leu Lys Ile Tyr Ser Gly Ser SerHis Gln 225 230 235 240 tgg ctt ccc atc tgt agc agc aac tgg aat gac tcctac tca gag aag 768 Trp Leu Pro Ile Cys Ser Ser Asn Trp Asn Asp Ser TyrSer Glu Lys 245 250 255 acc tgc cag cag ctg ggt ttc gag agt gct cac cggaca acc gag gtt 816 Thr Cys Gln Gln Leu Gly Phe Glu Ser Ala His Arg ThrThr Glu Val 260 265 270 gcc cac agg gat ttt gcc aac agc ttc tca atc ttgaga tac aac tcc 864 Ala His Arg Asp Phe Ala Asn Ser Phe Ser Ile Leu ArgTyr Asn Ser 275 280 285 acc atc cag gaa agc ctc cac agg tct gaa tgc ccttcc cag cgg tat 912 Thr Ile Gln Glu Ser Leu His Arg Ser Glu Cys Pro SerGln Arg Tyr 290 295 300 atc tcc ctc cag tgt tcc cac tgc gga ctg agg gccatg acc ggg cgg 960 Ile Ser Leu Gln Cys Ser His Cys Gly Leu Arg Ala MetThr Gly Arg 305 310 315 320 atc gtg gga ggg gcg ctg gcc tcg gat agc aagtgg cct tgg caa gtg 1008 Ile Val Gly Gly Ala Leu Ala Ser Asp Ser Lys TrpPro Trp Gln Val 325 330 335 agt ctg cac ttc ggc acc acc cac atc tgt ggaggc acg ctc att gac 1056 Ser Leu His Phe Gly Thr Thr His Ile Cys Gly GlyThr Leu Ile Asp 340 345 350 gcc cag tgg gtg ctc act gcc gcc cac tgc ttcttc gtg acc cgg gag 1104 Ala Gln Trp Val Leu Thr Ala Ala His Cys Phe PheVal Thr Arg Glu 355 360 365 aag gtc ctg gag ggc tgg aag gtg tac gcg ggcacc agc aac ctg cac 1152 Lys Val Leu Glu Gly Trp Lys Val Tyr Ala Gly ThrSer Asn Leu His 370 375 380 cag ttg cct gag gca gcc tcc att gcc gag atcatc atc aac agc aat 1200 Gln Leu Pro Glu Ala Ala Ser Ile Ala Glu Ile IleIle Asn Ser Asn 385 390 395 400 tac acc gat gag gag gac gac tat gac atcgcc ctc atg cgg ctg tcc 1248 Tyr Thr Asp Glu Glu Asp Asp Tyr Asp Ile AlaLeu Met Arg Leu Ser 405 410 415 aag ccc ctg acc ctg tcc gct cac atc caccct gct tgc ctc ccc atg 1296 Lys Pro Leu Thr Leu Ser Ala His Ile His ProAla Cys Leu Pro Met 420 425 430 cat gga cag acc ttt agc ctc aat gag acctgc tgg atc aca ggc ttt 1344 His Gly Gln Thr Phe Ser Leu Asn Glu Thr CysTrp Ile Thr Gly Phe 435 440 445 ggc aag acc agg gag aca gat gac aag acatcc ccc ttc ctc cgg gag 1392 Gly Lys Thr Arg Glu Thr Asp Asp Lys Thr SerPro Phe Leu Arg Glu 450 455 460 gtg cag gtc aat ctc atc gac ttc aag aaatgc aat gac tac ttg gtc 1440 Val Gln Val Asn Leu Ile Asp Phe Lys Lys CysAsn Asp Tyr Leu Val 465 470 475 480 tat gac agt tac ctt acc cca agg atgatg tgt gct ggg gac ctt cgt 1488 Tyr Asp Ser Tyr Leu Thr Pro Arg Met MetCys Ala Gly Asp Leu Arg 485 490 495 ggg ggc aga gac tcc tgc cag gga gacagc ggg ggg cct ctt gtc tgt 1536 Gly Gly Arg Asp Ser Cys Gln Gly Asp SerGly Gly Pro Leu Val Cys 500 505 510 gag cag aac aac cgc tgg tac ctg gcaggt gtc acc agc tgg ggc aca 1584 Glu Gln Asn Asn Arg Trp Tyr Leu Ala GlyVal Thr Ser Trp Gly Thr 515 520 525 ggc tgt ggc cag aga aac aaa cct ggtgtg tac acc aaa gtg aca gaa 1632 Gly Cys Gly Gln Arg Asn Lys Pro Gly ValTyr Thr Lys Val Thr Glu 530 535 540 gtt ctt ccc tgg att tac agc aag atggag agc gag gtg cga ttc ata 1680 Val Leu Pro Trp Ile Tyr Ser Lys Met GluSer Glu Val Arg Phe Ile 545 550 555 560 aaa tcc taa 1689 Lys Ser * <210>SEQ ID NO 24 <211> LENGTH: 562 <212> TYPE: PRT <213> ORGANISM: homosapien <220> FEATURE: <221> NAME/KEY: protease domain of endotheliase 2<222> LOCATION: (321)..(562) <400> SEQUENCE: 24 Met Glu Arg Asp Ser HisGly Asn Ala Ser Pro Ala Arg Thr Pro Ser 1 5 10 15 Ala Gly Ala Ser ProAla Gln Ala Ser Pro Ala Gly Thr Pro Pro Gly 20 25 30 Arg Ala Ser Pro AlaGln Ala Ser Pro Ala Gln Ala Ser Pro Ala Gly 35 40 45 Thr Pro Pro Gly ArgAla Ser Pro Ala Gln Ala Ser Pro Ala Gly Thr 50 55 60 Pro Pro Gly Arg AlaSer Pro Gly Arg Ala Ser Pro Ala Gln Ala Ser 65 70 75 80 Pro Ala Arg AlaSer Pro Ala Leu Ala Ser Leu Ser Arg Ser Ser Ser 85 90 95 Gly Arg Ser SerSer Ala Arg Ser Ala Ser Val Thr Thr Ser Pro Thr 100 105 110 Arg Val TyrLeu Val Arg Ala Thr Pro Val Gly Ala Val Pro Ile Arg 115 120 125 Ser SerPro Ala Arg Ser Ala Pro Ala Thr Arg Ala Thr Arg Glu Ser 130 135 140 ProGly Thr Ser Leu Pro Lys Phe Thr Trp Arg Glu Gly Gln Lys Gln 145 150 155160 Leu Pro Leu Ile Gly Cys Val Leu Leu Leu Ile Ala Leu Val Val Ser 165170 175 Leu Ile Ile Leu Phe Gln Phe Trp Gln Gly His Thr Gly Ile Arg Tyr180 185 190 Lys Glu Gln Arg Glu Ser Cys Pro Lys His Ala Val Arg Cys AspGly 195 200 205 Val Val Asp Cys Lys Leu Lys Ser Asp Glu Leu Gly Cys ValArg Phe 210 215 220 Asp Trp Asp Lys Ser Leu Leu Lys Ile Tyr Ser Gly SerSer His Gln 225 230 235 240 Trp Leu Pro Ile Cys Ser Ser Asn Trp Asn AspSer Tyr Ser Glu Lys 245 250 255 Thr Cys Gln Gln Leu Gly Phe Glu Ser AlaHis Arg Thr Thr Glu Val 260 265 270 Ala His Arg Asp Phe Ala Asn Ser PheSer Ile Leu Arg Tyr Asn Ser 275 280 285 Thr Ile Gln Glu Ser Leu His ArgSer Glu Cys Pro Ser Gln Arg Tyr 290 295 300 Ile Ser Leu Gln Cys Ser HisCys Gly Leu Arg Ala Met Thr Gly Arg 305 310 315 320 Ile Val Gly Gly AlaLeu Ala Ser Asp Ser Lys Trp Pro Trp Gln Val 325 330 335 Ser Leu His PheGly Thr Thr His Ile Cys Gly Gly Thr Leu Ile Asp 340 345 350 Ala Gln TrpVal Leu Thr Ala Ala His Cys Phe Phe Val Thr Arg Glu 355 360 365 Lys ValLeu Glu Gly Trp Lys Val Tyr Ala Gly Thr Ser Asn Leu His 370 375 380 GlnLeu Pro Glu Ala Ala Ser Ile Ala Glu Ile Ile Ile Asn Ser Asn 385 390 395400 Tyr Thr Asp Glu Glu Asp Asp Tyr Asp Ile Ala Leu Met Arg Leu Ser 405410 415 Lys Pro Leu Thr Leu Ser Ala His Ile His Pro Ala Cys Leu Pro Met420 425 430 His Gly Gln Thr Phe Ser Leu Asn Glu Thr Cys Trp Ile Thr GlyPhe 435 440 445 Gly Lys Thr Arg Glu Thr Asp Asp Lys Thr Ser Pro Phe LeuArg Glu 450 455 460 Val Gln Val Asn Leu Ile Asp Phe Lys Lys Cys Asn AspTyr Leu Val 465 470 475 480 Tyr Asp Ser Tyr Leu Thr Pro Arg Met Met CysAla Gly Asp Leu Arg 485 490 495 Gly Gly Arg Asp Ser Cys Gln Gly Asp SerGly Gly Pro Leu Val Cys 500 505 510 Glu Gln Asn Asn Arg Trp Tyr Leu AlaGly Val Thr Ser Trp Gly Thr 515 520 525 Gly Cys Gly Gln Arg Asn Lys ProGly Val Tyr Thr Lys Val Thr Glu 530 535 540 Val Leu Pro Trp Ile Tyr SerLys Met Glu Ser Glu Val Arg Phe Ile 545 550 555 560 Lys Ser <210> SEQ IDNO 25 <211> LENGTH: 2067 <212> TYPE: DNA <213> ORGANISM: Homo Sapien<220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (1)...(2067) <223>OTHER INFORMATION: Nucleic acid encoding (endotheliase 2-L) protein<400> SEQUENCE: 25 atg gag agg gac agc cac ggg aat gca tct cca gca agaaca cct tca 48 Met Glu Arg Asp Ser His Gly Asn Ala Ser Pro Ala Arg ThrPro Ser 1 5 10 15 gct gga gca tct cca gcc cag gca tct cca gct ggg acacct cca ggc 96 Ala Gly Ala Ser Pro Ala Gln Ala Ser Pro Ala Gly Thr ProPro Gly 20 25 30 cgg gca tct cca gcc cag gca tct cca gcc cag gca tct ccagct ggg 144 Arg Ala Ser Pro Ala Gln Ala Ser Pro Ala Gln Ala Ser Pro AlaGly 35 40 45 aca cct ccg ggc cgg gca tct cca gcc cag gca tct cca gct ggtaca 192 Thr Pro Pro Gly Arg Ala Ser Pro Ala Gln Ala Ser Pro Ala Gly Thr50 55 60 cct cca ggc cgg gca tct cca ggc cgg gca tct cca gcc cag gca tct240 Pro Pro Gly Arg Ala Ser Pro Gly Arg Ala Ser Pro Ala Gln Ala Ser 6570 75 80 cca gcc cgg gca tct ccg gct ctg gca tca ctt tcc agg tcc tca tcc288 Pro Ala Arg Ala Ser Pro Ala Leu Ala Ser Leu Ser Arg Ser Ser Ser 8590 95 ggc agg tca tca tcc gcc agg tca gcc tcg gtg aca acc tcc cca acc336 Gly Arg Ser Ser Ser Ala Arg Ser Ala Ser Val Thr Thr Ser Pro Thr 100105 110 aga gtg tac ctt gtt aga gca aca cca gtg ggg gct gta ccc atc cga384 Arg Val Tyr Leu Val Arg Ala Thr Pro Val Gly Ala Val Pro Ile Arg 115120 125 tca tct cct gcc agg tca gca cca gca acc agg gcc acc agg gag agc432 Ser Ser Pro Ala Arg Ser Ala Pro Ala Thr Arg Ala Thr Arg Glu Ser 130135 140 cca ggt acg agc ctg ccc aag ttc acc tgg cgg gag ggc cag aag cag480 Pro Gly Thr Ser Leu Pro Lys Phe Thr Trp Arg Glu Gly Gln Lys Gln 145150 155 160 cta ccg ctc atc ggg tgc gtg ctc ctc ctc att gcc ctg gtg gtttcg 528 Leu Pro Leu Ile Gly Cys Val Leu Leu Leu Ile Ala Leu Val Val Ser165 170 175 ctc atc atc ctc ttc cag ttc tgg cag ggc cac aca ggg atc aggtac 576 Leu Ile Ile Leu Phe Gln Phe Trp Gln Gly His Thr Gly Ile Arg Tyr180 185 190 aag gag cag agg gag agc tgt ccc aag cac gct gtt cgc tgt gacggg 624 Lys Glu Gln Arg Glu Ser Cys Pro Lys His Ala Val Arg Cys Asp Gly195 200 205 gtg gtg gac tgc aag ctg aag agt gac gag ctg ggc tgc gtg aggttt 672 Val Val Asp Cys Lys Leu Lys Ser Asp Glu Leu Gly Cys Val Arg Phe210 215 220 gac tgg gac aag tct ctg ctt aaa atc tac tct ggg tcc tcc catcag 720 Asp Trp Asp Lys Ser Leu Leu Lys Ile Tyr Ser Gly Ser Ser His Gln225 230 235 240 tgg ctt ccc atc tgt agc agc aac tgg aat gac tcc tac tcagag aag 768 Trp Leu Pro Ile Cys Ser Ser Asn Trp Asn Asp Ser Tyr Ser GluLys 245 250 255 acc tgc cag cag ctg ggt ttc gag agt gct cac cgg aca accgag gtt 816 Thr Cys Gln Gln Leu Gly Phe Glu Ser Ala His Arg Thr Thr GluVal 260 265 270 gcc cac agg gat ttt gcc aac agc ttc tca atc ttg aga tacaac tcc 864 Ala His Arg Asp Phe Ala Asn Ser Phe Ser Ile Leu Arg Tyr AsnSer 275 280 285 acc atc cag gaa agc ctc cac agg tct gaa tgc cct tcc cagcgg tat 912 Thr Ile Gln Glu Ser Leu His Arg Ser Glu Cys Pro Ser Gln ArgTyr 290 295 300 atc tcc ctc cag tgt tcc cac tgc gga ctg agg gcc atg accggg cgg 960 Ile Ser Leu Gln Cys Ser His Cys Gly Leu Arg Ala Met Thr GlyArg 305 310 315 320 atc gtg gga ggg gcg ctg gcc tcg gat agc aag tgg ccttgg caa gtg 1008 Ile Val Gly Gly Ala Leu Ala Ser Asp Ser Lys Trp Pro TrpGln Val 325 330 335 agt ctg cac ttc ggc acc acc cac atc tgt gga ggc acgctc att gac 1056 Ser Leu His Phe Gly Thr Thr His Ile Cys Gly Gly Thr LeuIle Asp 340 345 350 gcc cag tgg gtg ctc act gcc gcc cac tgc ttc ttc gtgacc cgg gag 1104 Ala Gln Trp Val Leu Thr Ala Ala His Cys Phe Phe Val ThrArg Glu 355 360 365 aag gtc ctg gag ggc tgg aag gtg tac gcg ggc acc agcaac ctg cac 1152 Lys Val Leu Glu Gly Trp Lys Val Tyr Ala Gly Thr Ser AsnLeu His 370 375 380 cag ttg cct gag gca gcc tcc att gcc gag atc atc atcaac agc aat 1200 Gln Leu Pro Glu Ala Ala Ser Ile Ala Glu Ile Ile Ile AsnSer Asn 385 390 395 400 tac acc gat gag gag gac gac tat gac atc gcc ctcatg cgg ctg tcc 1248 Tyr Thr Asp Glu Glu Asp Asp Tyr Asp Ile Ala Leu MetArg Leu Ser 405 410 415 aag ccc ctg acc ctg tcc gct cac atc cac cct gcttgc ctc ccc atg 1296 Lys Pro Leu Thr Leu Ser Ala His Ile His Pro Ala CysLeu Pro Met 420 425 430 cat gga cag acc ttt agc ctc aat gag acc tgc tggatc aca ggc ttt 1344 His Gly Gln Thr Phe Ser Leu Asn Glu Thr Cys Trp IleThr Gly Phe 435 440 445 ggc aag acc agg gag aca gat gac aag aca tcc cccttc ctc cgg gag 1392 Gly Lys Thr Arg Glu Thr Asp Asp Lys Thr Ser Pro PheLeu Arg Glu 450 455 460 gtg cag gtc aat ctc atc gac ttc aag aaa tgc aatgac tac ttg gtc 1440 Val Gln Val Asn Leu Ile Asp Phe Lys Lys Cys Asn AspTyr Leu Val 465 470 475 480 tat gac agt tac ctt acc cca agg atg atg tgtgct ggg gac ctt cgt 1488 Tyr Asp Ser Tyr Leu Thr Pro Arg Met Met Cys AlaGly Asp Leu Arg 485 490 495 ggg ggc aga gac tcc tgc cag gga gac agc gggggg cct ctt gtc tgt 1536 Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly GlyPro Leu Val Cys 500 505 510 gag cag aac aac cgc tgg tac ctg gca ggt gtcacc agc tgg ggc aca 1584 Glu Gln Asn Asn Arg Trp Tyr Leu Ala Gly Val ThrSer Trp Gly Thr 515 520 525 ggc tgt ggc cag aga aac aaa cct ggt gtg tacacc aaa gtg aca gaa 1632 Gly Cys Gly Gln Arg Asn Lys Pro Gly Val Tyr ThrLys Val Thr Glu 530 535 540 gtt ctt ccc tgg att tac agc aag atg gag aacaga gct cag cgg gtt 1680 Val Leu Pro Trp Ile Tyr Ser Lys Met Glu Asn ArgAla Gln Arg Val 545 550 555 560 gaa aaa gcg tgg acc tac agg cca ggc aggcag ttg ctg ggc aga tgt 1728 Glu Lys Ala Trp Thr Tyr Arg Pro Gly Arg GlnLeu Leu Gly Arg Cys 565 570 575 tct ccc aga agt att ttt ttg tgt aag gttgca atg gac ttt gaa aac 1776 Ser Pro Arg Ser Ile Phe Leu Cys Lys Val AlaMet Asp Phe Glu Asn 580 585 590 gtt tca gtt tct gca gag gat ttt gtg atagtt ttt gtt atc aag cat 1824 Val Ser Val Ser Ala Glu Asp Phe Val Ile ValPhe Val Ile Lys His 595 600 605 tta tgc atg gga atc cgc tct tca tgg cctttc cca gct ctg ttt gtt 1872 Leu Cys Met Gly Ile Arg Ser Ser Trp Pro PhePro Ala Leu Phe Val 610 615 620 tta gtc ttt ttg att ttc ttt ttg ttg ttgttg ttg tct ttt tta aaa 1920 Leu Val Phe Leu Ile Phe Phe Leu Leu Leu LeuLeu Ser Phe Leu Lys 625 630 635 640 aac aca agt gac tcc att ttg act ctgaca act ttc aca gct gtc acc 1968 Asn Thr Ser Asp Ser Ile Leu Thr Leu ThrThr Phe Thr Ala Val Thr 645 650 655 aga atg ctc cct gag aac tac cat tctttc cct ttc cca ctt aaa ata 2016 Arg Met Leu Pro Glu Asn Tyr His Ser PhePro Phe Pro Leu Lys Ile 660 665 670 ttt cat cag aac ctc act act atc ataaaa gag tat aaa gta ata aaa 2064 Phe His Gln Asn Leu Thr Thr Ile Ile LysGlu Tyr Lys Val Ile Lys 675 680 685 taa 2067 <210> SEQ ID NO 26 <211>LENGTH: 688 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <220> FEATURE:<221> NAME/KEY: protease domain <222> LOCATION: (321)..(688) <400>SEQUENCE: 26 Met Glu Arg Asp Ser His Gly Asn Ala Ser Pro Ala Arg Thr ProSer 1 5 10 15 Ala Gly Ala Ser Pro Ala Gln Ala Ser Pro Ala Gly Thr ProPro Gly 20 25 30 Arg Ala Ser Pro Ala Gln Ala Ser Pro Ala Gln Ala Ser ProAla Gly 35 40 45 Thr Pro Pro Gly Arg Ala Ser Pro Ala Gln Ala Ser Pro AlaGly Thr 50 55 60 Pro Pro Gly Arg Ala Ser Pro Gly Arg Ala Ser Pro Ala GlnAla Ser 65 70 75 80 Pro Ala Arg Ala Ser Pro Ala Leu Ala Ser Leu Ser ArgSer Ser Ser 85 90 95 Gly Arg Ser Ser Ser Ala Arg Ser Ala Ser Val Thr ThrSer Pro Thr 100 105 110 Arg Val Tyr Leu Val Arg Ala Thr Pro Val Gly AlaVal Pro Ile Arg 115 120 125 Ser Ser Pro Ala Arg Ser Ala Pro Ala Thr ArgAla Thr Arg Glu Ser 130 135 140 Pro Gly Thr Ser Leu Pro Lys Phe Thr TrpArg Glu Gly Gln Lys Gln 145 150 155 160 Leu Pro Leu Ile Gly Cys Val LeuLeu Leu Ile Ala Leu Val Val Ser 165 170 175 Leu Ile Ile Leu Phe Gln PheTrp Gln Gly His Thr Gly Ile Arg Tyr 180 185 190 Lys Glu Gln Arg Glu SerCys Pro Lys His Ala Val Arg Cys Asp Gly 195 200 205 Val Val Asp Cys LysLeu Lys Ser Asp Glu Leu Gly Cys Val Arg Phe 210 215 220 Asp Trp Asp LysSer Leu Leu Lys Ile Tyr Ser Gly Ser Ser His Gln 225 230 235 240 Trp LeuPro Ile Cys Ser Ser Asn Trp Asn Asp Ser Tyr Ser Glu Lys 245 250 255 ThrCys Gln Gln Leu Gly Phe Glu Ser Ala His Arg Thr Thr Glu Val 260 265 270Ala His Arg Asp Phe Ala Asn Ser Phe Ser Ile Leu Arg Tyr Asn Ser 275 280285 Thr Ile Gln Glu Ser Leu His Arg Ser Glu Cys Pro Ser Gln Arg Tyr 290295 300 Ile Ser Leu Gln Cys Ser His Cys Gly Leu Arg Ala Met Thr Gly Arg305 310 315 320 Ile Val Gly Gly Ala Leu Ala Ser Asp Ser Lys Trp Pro TrpGln Val 325 330 335 Ser Leu His Phe Gly Thr Thr His Ile Cys Gly Gly ThrLeu Ile Asp 340 345 350 Ala Gln Trp Val Leu Thr Ala Ala His Cys Phe PheVal Thr Arg Glu 355 360 365 Lys Val Leu Glu Gly Trp Lys Val Tyr Ala GlyThr Ser Asn Leu His 370 375 380 Gln Leu Pro Glu Ala Ala Ser Ile Ala GluIle Ile Ile Asn Ser Asn 385 390 395 400 Tyr Thr Asp Glu Glu Asp Asp TyrAsp Ile Ala Leu Met Arg Leu Ser 405 410 415 Lys Pro Leu Thr Leu Ser AlaHis Ile His Pro Ala Cys Leu Pro Met 420 425 430 His Gly Gln Thr Phe SerLeu Asn Glu Thr Cys Trp Ile Thr Gly Phe 435 440 445 Gly Lys Thr Arg GluThr Asp Asp Lys Thr Ser Pro Phe Leu Arg Glu 450 455 460 Val Gln Val AsnLeu Ile Asp Phe Lys Lys Cys Asn Asp Tyr Leu Val 465 470 475 480 Tyr AspSer Tyr Leu Thr Pro Arg Met Met Cys Ala Gly Asp Leu Arg 485 490 495 GlyGly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys 500 505 510Glu Gln Asn Asn Arg Trp Tyr Leu Ala Gly Val Thr Ser Trp Gly Thr 515 520525 Gly Cys Gly Gln Arg Asn Lys Pro Gly Val Tyr Thr Lys Val Thr Glu 530535 540 Val Leu Pro Trp Ile Tyr Ser Lys Met Glu Asn Arg Ala Gln Arg Val545 550 555 560 Glu Lys Ala Trp Thr Tyr Arg Pro Gly Arg Gln Leu Leu GlyArg Cys 565 570 575 Ser Pro Arg Ser Ile Phe Leu Cys Lys Val Ala Met AspPhe Glu Asn 580 585 590 Val Ser Val Ser Ala Glu Asp Phe Val Ile Val PheVal Ile Lys His 595 600 605 Leu Cys Met Gly Ile Arg Ser Ser Trp Pro PhePro Ala Leu Phe Val 610 615 620 Leu Val Phe Leu Ile Phe Phe Leu Leu LeuLeu Leu Ser Phe Leu Lys 625 630 635 640 Asn Thr Ser Asp Ser Ile Leu ThrLeu Thr Thr Phe Thr Ala Val Thr 645 650 655 Arg Met Leu Pro Glu Asn TyrHis Ser Phe Pro Phe Pro Leu Lys Ile 660 665 670 Phe His Gln Asn Leu ThrThr Ile Ile Lys Glu Tyr Lys Val Ile Lys 675 680 685 <210> SEQ ID NO 27<211> LENGTH: 1471 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (626)...(1324)<223> OTHER INFORMATION: DESC1 gene <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (56)...(1324) <223> OTHER INFORMATION: protease domain<400> SEQUENCE: 27 tgacttggat gtagacctcg accttcacag gactcttcattgctggttgg caatg atg 58 Met 1 tat cgg cca gat gtg gtg agg gct agg aaaaga gtt tgt tgg gaa ccc 106 Tyr Arg Pro Asp Val Val Arg Ala Arg Lys ArgVal Cys Trp Glu Pro 5 10 15 tgg gtt atc ggc ctc gtc ats ttc ata tcc ctgatt gtc ctg gca gtg 154 Trp Val Ile Gly Leu Val Xaa Phe Ile Ser Leu IleVal Leu Ala Val 20 25 30 tgc att gga stc act gtt cat tat gtg aga tat aatcaa aag aag acc 202 Cys Ile Gly Xaa Thr Val His Tyr Val Arg Tyr Asn GlnLys Lys Thr 35 40 45 tac aat tac tat agc aca ttg tca ttt aca act gac aaacta tat gct 250 Tyr Asn Tyr Tyr Ser Thr Leu Ser Phe Thr Thr Asp Lys LeuTyr Ala 50 55 60 65 gag ttt ggc aga gag gct tct aac aat ttt aca gaa atgagc cag aga 298 Glu Phe Gly Arg Glu Ala Ser Asn Asn Phe Thr Glu Met SerGln Arg 70 75 80 ctt gaa tca atg gtg aaa aat gca ttt tat aaa tct cca ttaagg gaa 346 Leu Glu Ser Met Val Lys Asn Ala Phe Tyr Lys Ser Pro Leu ArgGlu 85 90 95 gaa ttt gtc aag tct cag gtt atc aag ttc agt caa cag aag catgga 394 Glu Phe Val Lys Ser Gln Val Ile Lys Phe Ser Gln Gln Lys His Gly100 105 110 gtg ttg gct cat atg ctg ttg att tgt aga ttt cac tct act gaggat 442 Val Leu Ala His Met Leu Leu Ile Cys Arg Phe His Ser Thr Glu Asp115 120 125 cct gaa act gta gat aaa att gtt caa ctt gtt tta cat gaa aagctg 490 Pro Glu Thr Val Asp Lys Ile Val Gln Leu Val Leu His Glu Lys Leu130 135 140 145 caa gat gct gta gga ccc cct aaa gta gat cct cac tca gttaaa att 538 Gln Asp Ala Val Gly Pro Pro Lys Val Asp Pro His Ser Val LysIle 150 155 160 aaa aaa atc aac aag aca gaa aca gac agc tat cta aac cattgc tgc 586 Lys Lys Ile Asn Lys Thr Glu Thr Asp Ser Tyr Leu Asn His CysCys 165 170 175 gga aca cga aga agt aaa act cta ggt cag agt ctc agg atcgtt ggt 634 Gly Thr Arg Arg Ser Lys Thr Leu Gly Gln Ser Leu Arg Ile ValGly 180 185 190 ggg aca gaa gta gaa gag ggt gaa tgg ccc tgg cag gct agcctg cag 682 Gly Thr Glu Val Glu Glu Gly Glu Trp Pro Trp Gln Ala Ser LeuGln 195 200 205 tgg gat ggg agt cat cgc tgt gga gca acc tta att aat gccaca tgg 730 Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu Ile Asn Ala ThrTrp 210 215 220 225 ctt gtg agt gct gct cac tgt ttt aca aca tat aag aaccct gcc aga 778 Leu Val Ser Ala Ala His Cys Phe Thr Thr Tyr Lys Asn ProAla Arg 230 235 240 tgg act gct tcc ttt gga gta aca ata aaa cct tcg aaaatg aaa cgg 826 Trp Thr Ala Ser Phe Gly Val Thr Ile Lys Pro Ser Lys MetLys Arg 245 250 255 ggt ctc cgg aga ata att gtc cat gaa aaa tac aaa caccca tca cat 874 Gly Leu Arg Arg Ile Ile Val His Glu Lys Tyr Lys His ProSer His 260 265 270 gac tat gat att tct ctt gca gag ctt tct agc cct gttccc tac aca 922 Asp Tyr Asp Ile Ser Leu Ala Glu Leu Ser Ser Pro Val ProTyr Thr 275 280 285 aat gca gta cat aga gtt tgt ctc cct gat gca tcc tatgag ttt caa 970 Asn Ala Val His Arg Val Cys Leu Pro Asp Ala Ser Tyr GluPhe Gln 290 295 300 305 cca ggt gat gtg atg ttt gtg aca gga ttt gga gcactg aaa aat gat 1018 Pro Gly Asp Val Met Phe Val Thr Gly Phe Gly Ala LeuLys Asn Asp 310 315 320 ggt tac agt caa aat cat ctt cga caa gca cag gtgact ctc ata gac 1066 Gly Tyr Ser Gln Asn His Leu Arg Gln Ala Gln Val ThrLeu Ile Asp 325 330 335 gct aca act tgc aat gaa cct caa gct tac aat gacgcc ata act cct 1114 Ala Thr Thr Cys Asn Glu Pro Gln Ala Tyr Asn Asp AlaIle Thr Pro 340 345 350 aga atg tta tgt gct ggc tcc tta gaa gga aaa acagat gca tgc cag 1162 Arg Met Leu Cys Ala Gly Ser Leu Glu Gly Lys Thr AspAla Cys Gln 355 360 365 ggt gac tct gga gga cca ctg gtt agt tca gat gctaga gat atc tgg 1210 Gly Asp Ser Gly Gly Pro Leu Val Ser Ser Asp Ala ArgAsp Ile Trp 370 375 380 385 tac ctt gct gga ata gtg agc tsg gga gat gaatgt gcg aaa ccc aac 1258 Tyr Leu Ala Gly Ile Val Ser Xaa Gly Asp Glu CysAla Lys Pro Asn 390 395 400 aag cct ggt gtt tat act aga gtt acg gcc ttgcgg gac tgg att act 1306 Lys Pro Gly Val Tyr Thr Arg Val Thr Ala Leu ArgAsp Trp Ile Thr 405 410 415 tca aaa act ggt atc taa gagagaaaagcctcatggaa cagataacat 1354 Ser Lys Thr Gly Ile * 420 ttttttttgttttttgggtg tggaggccat ttttagagat acagaattgg agaagacttg 1414 caaaacagctagatttgact gatctcaata aactgtttgc ttgatgcaaa aaaaaaa 1471 <210> SEQ ID NO28 <211> LENGTH: 4933 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (94)...(3222) <223> OTHERINFORMATION: Nucleotide sequence encoding corin <300> PUBLICATIONINFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank AF133845 <309>DATABASE ENTRY DATE: 1999-05-24 <400> SEQUENCE: 28 aaatcatccg tagtgcctccccgggggaca cgtagaggag agaaaagcga ccaagataaa 60 agtggacaga agaataagcgagacttttta tcc atg aaa cag tct cct gcc ctc 114 Met Lys Gln Ser Pro AlaLeu 1 5 gct ccg gaa gag cgc tac cgc aga gcc ggg tcc cca aag ccg gtc ttg162 Ala Pro Glu Glu Arg Tyr Arg Arg Ala Gly Ser Pro Lys Pro Val Leu 1015 20 aga gct gat gac aat aac atg ggc aat ggc tgc tct cag aag ctg gcg210 Arg Ala Asp Asp Asn Asn Met Gly Asn Gly Cys Ser Gln Lys Leu Ala 2530 35 act gct aac ctc ctc cgg ttc cta ttg ctg gtc ctg att cca tgt atc258 Thr Ala Asn Leu Leu Arg Phe Leu Leu Leu Val Leu Ile Pro Cys Ile 4045 50 55 tgt gct ctc gtt ctc ttg ctg gtg atc ctg ctt tcc tat gtt gga aca306 Cys Ala Leu Val Leu Leu Leu Val Ile Leu Leu Ser Tyr Val Gly Thr 6065 70 tta caa aag gtc tat ttt aaa tca aat ggg agt gaa cct ttg gtc act354 Leu Gln Lys Val Tyr Phe Lys Ser Asn Gly Ser Glu Pro Leu Val Thr 7580 85 gat ggt gaa atc caa ggg tcc gat gtt att ctt aca aat aca att tat402 Asp Gly Glu Ile Gln Gly Ser Asp Val Ile Leu Thr Asn Thr Ile Tyr 9095 100 aac cag agc act gtg gtg tct act gca cat ccc gac caa cac gtt cca450 Asn Gln Ser Thr Val Val Ser Thr Ala His Pro Asp Gln His Val Pro 105110 115 gcc tgg act acg gat gct tct ctc cca ggg gac caa agt cac agg aat498 Ala Trp Thr Thr Asp Ala Ser Leu Pro Gly Asp Gln Ser His Arg Asn 120125 130 135 aca agt gcc tgt atg aac atc acc cac agc cag tgt cag atg ctgccc 546 Thr Ser Ala Cys Met Asn Ile Thr His Ser Gln Cys Gln Met Leu Pro140 145 150 tac cac gcc acg ctg aca cct ctc ctc tca gtt gtc aga aac atggaa 594 Tyr His Ala Thr Leu Thr Pro Leu Leu Ser Val Val Arg Asn Met Glu155 160 165 atg gaa aag ttc ctc aag ttt ttc aca tat ctc cat cgc ctc agttgc 642 Met Glu Lys Phe Leu Lys Phe Phe Thr Tyr Leu His Arg Leu Ser Cys170 175 180 tat caa cat atc atg ctg ttt ggc tgt acc ctc gcc ttc cct gagtgc 690 Tyr Gln His Ile Met Leu Phe Gly Cys Thr Leu Ala Phe Pro Glu Cys185 190 195 atc att gat ggc gat gac agt cat gga ctc ctg ccc tgt agg tccttc 738 Ile Ile Asp Gly Asp Asp Ser His Gly Leu Leu Pro Cys Arg Ser Phe200 205 210 215 tgt gag gct gca aaa gaa ggc tgt gaa tca gtc ctg ggg atggtg aat 786 Cys Glu Ala Ala Lys Glu Gly Cys Glu Ser Val Leu Gly Met ValAsn 220 225 230 tac tcc tgg ccg gat ttc ctc aga tgc tcc cag ttt aga aaccaa act 834 Tyr Ser Trp Pro Asp Phe Leu Arg Cys Ser Gln Phe Arg Asn GlnThr 235 240 245 gaa agc agc aat gtc agc aga att tgc ttc tca cct cag caggaa aac 882 Glu Ser Ser Asn Val Ser Arg Ile Cys Phe Ser Pro Gln Gln GluAsn 250 255 260 gga aag caa ttg ctc tgt gga agg ggt gag aac ttt ctg tgtgcc agt 930 Gly Lys Gln Leu Leu Cys Gly Arg Gly Glu Asn Phe Leu Cys AlaSer 265 270 275 gga atc tgc atc ccc ggg aaa ctg caa tgt aat ggc tac aacgac tgt 978 Gly Ile Cys Ile Pro Gly Lys Leu Gln Cys Asn Gly Tyr Asn AspCys 280 285 290 295 gac gac tgg agt gac gag gct cat tgc aac tgc agc gagaat ctg ttt 1026 Asp Asp Trp Ser Asp Glu Ala His Cys Asn Cys Ser Glu AsnLeu Phe 300 305 310 cac tgt cac aca ggc aag tgc ctt aat tac agc ctt gtgtgt gat gga 1074 His Cys His Thr Gly Lys Cys Leu Asn Tyr Ser Leu Val CysAsp Gly 315 320 325 tat gat gac tgt ggg gat ttg agt gat gag caa aac tgtgat tgc aat 1122 Tyr Asp Asp Cys Gly Asp Leu Ser Asp Glu Gln Asn Cys AspCys Asn 330 335 340 ccc aca aca gag cat cgc tgc ggg gac ggg cgc tgc atcgcc atg gag 1170 Pro Thr Thr Glu His Arg Cys Gly Asp Gly Arg Cys Ile AlaMet Glu 345 350 355 tgg gtg tgt gat ggt gac cac gac tgt gtg gat aag tccgac gag gtc 1218 Trp Val Cys Asp Gly Asp His Asp Cys Val Asp Lys Ser AspGlu Val 360 365 370 375 aac tgc tcc tgt cac agc cag ggt ctg gtg gaa tgcaga aat gga caa 1266 Asn Cys Ser Cys His Ser Gln Gly Leu Val Glu Cys ArgAsn Gly Gln 380 385 390 tgt atc ccc agc acg ttt caa tgt gat ggt gac gaggac tgc aag gat 1314 Cys Ile Pro Ser Thr Phe Gln Cys Asp Gly Asp Glu AspCys Lys Asp 395 400 405 ggg agt gat gag gag aac tgc agc gtc att cag acttca tgt caa gaa 1362 Gly Ser Asp Glu Glu Asn Cys Ser Val Ile Gln Thr SerCys Gln Glu 410 415 420 gga gac caa aga tgc ctc tac aat ccc tgc ctt gattca tgt ggt ggt 1410 Gly Asp Gln Arg Cys Leu Tyr Asn Pro Cys Leu Asp SerCys Gly Gly 425 430 435 agc tct ctc tgt gac ccg aac aac agt ctg aat aactgt agt caa tgt 1458 Ser Ser Leu Cys Asp Pro Asn Asn Ser Leu Asn Asn CysSer Gln Cys 440 445 450 455 gaa cca att aca ttg gaa ctc tgc atg aat ttgccc tac aac agt aca 1506 Glu Pro Ile Thr Leu Glu Leu Cys Met Asn Leu ProTyr Asn Ser Thr 460 465 470 agt tat cca aat tat ttt ggc cac agg act caaaag gaa gca tcc atc 1554 Ser Tyr Pro Asn Tyr Phe Gly His Arg Thr Gln LysGlu Ala Ser Ile 475 480 485 agc tgg gag tct tct ctt ttc cct gca ctt gttcaa acc aac tgt tat 1602 Ser Trp Glu Ser Ser Leu Phe Pro Ala Leu Val GlnThr Asn Cys Tyr 490 495 500 aaa tac ctc atg ttc ttt tct tgc acc att ttggta cca aaa tgt gat 1650 Lys Tyr Leu Met Phe Phe Ser Cys Thr Ile Leu ValPro Lys Cys Asp 505 510 515 gtg aat aca ggc gag cgt atc cct cct tgc agggca ttg tgt gaa cac 1698 Val Asn Thr Gly Glu Arg Ile Pro Pro Cys Arg AlaLeu Cys Glu His 520 525 530 535 tct aaa gaa cgc tgt gag tct gtt ctt gggatt gtg ggc cta cag tgg 1746 Ser Lys Glu Arg Cys Glu Ser Val Leu Gly IleVal Gly Leu Gln Trp 540 545 550 cct gaa gac aca gat tgc agt caa ttt ccagag gaa aat tca gac aat 1794 Pro Glu Asp Thr Asp Cys Ser Gln Phe Pro GluGlu Asn Ser Asp Asn 555 560 565 caa acc tgc ctg atg cct gat gaa tat gtggaa gaa tgc tca cct agt 1842 Gln Thr Cys Leu Met Pro Asp Glu Tyr Val GluGlu Cys Ser Pro Ser 570 575 580 cat ttc aag tgc cgc tca gga cag tgt gttctg gct tcc aga aga tgt 1890 His Phe Lys Cys Arg Ser Gly Gln Cys Val LeuAla Ser Arg Arg Cys 585 590 595 gat ggc cag gcc gac tgt gac gat gac agtgat gag gaa aac tgt ggt 1938 Asp Gly Gln Ala Asp Cys Asp Asp Asp Ser AspGlu Glu Asn Cys Gly 600 605 610 615 tgt aaa gag aga gat ctt tgg gaa tgtcca tcc aat aaa caa tgt ttg 1986 Cys Lys Glu Arg Asp Leu Trp Glu Cys ProSer Asn Lys Gln Cys Leu 620 625 630 aag cac aca gtg atc tgc gat ggg ttccca gac tgc cct gat tac atg 2034 Lys His Thr Val Ile Cys Asp Gly Phe ProAsp Cys Pro Asp Tyr Met 635 640 645 gac gag aaa aac tgc tca ttt tgc caagat gat gag ctg gaa tgt gca 2082 Asp Glu Lys Asn Cys Ser Phe Cys Gln AspAsp Glu Leu Glu Cys Ala 650 655 660 aac cat gcg tgt gtg tca cgt gac ctgtgg tgt gat ggt gaa gcc gac 2130 Asn His Ala Cys Val Ser Arg Asp Leu TrpCys Asp Gly Glu Ala Asp 665 670 675 tgc tca gac agt tca gat gaa tgg gactgt gtg acc ctc tct ata aat 2178 Cys Ser Asp Ser Ser Asp Glu Trp Asp CysVal Thr Leu Ser Ile Asn 680 685 690 695 gtg aac tcc tct tcc ttt ctg atggtt cac aga gct gcc aca gaa cac 2226 Val Asn Ser Ser Ser Phe Leu Met ValHis Arg Ala Ala Thr Glu His 700 705 710 cat gtg tgt gca gat ggc tgg caggag ata ttg agt cag ctg gcc tgc 2274 His Val Cys Ala Asp Gly Trp Gln GluIle Leu Ser Gln Leu Ala Cys 715 720 725 aag cag atg ggt tta gga gaa ccatct gtg acc aaa ttg ata cag gaa 2322 Lys Gln Met Gly Leu Gly Glu Pro SerVal Thr Lys Leu Ile Gln Glu 730 735 740 cag gag aaa gag ccg cgg tgg ctgaca tta cac tcc aac tgg gag agc 2370 Gln Glu Lys Glu Pro Arg Trp Leu ThrLeu His Ser Asn Trp Glu Ser 745 750 755 ctc aat ggg acc act tta cat gaactt cta gta aat ggg cag tct tgt 2418 Leu Asn Gly Thr Thr Leu His Glu LeuLeu Val Asn Gly Gln Ser Cys 760 765 770 775 gag agc aga agt aaa att tctctt ctg tgt act aaa caa gac tgt ggg 2466 Glu Ser Arg Ser Lys Ile Ser LeuLeu Cys Thr Lys Gln Asp Cys Gly 780 785 790 cgc cgc cct gct gcc cga atgaac aaa agg atc ctt gga ggt cgg acg 2514 Arg Arg Pro Ala Ala Arg Met AsnLys Arg Ile Leu Gly Gly Arg Thr 795 800 805 agt cgc cct gga agg tgg ccatgg cag tgt tct ctg cag agt gaa ccc 2562 Ser Arg Pro Gly Arg Trp Pro TrpGln Cys Ser Leu Gln Ser Glu Pro 810 815 820 agt gga cat atc tgt ggc tgtgtc ctc att gcc aag aag tgg gtt ctg 2610 Ser Gly His Ile Cys Gly Cys ValLeu Ile Ala Lys Lys Trp Val Leu 825 830 835 aca gtt gcc cac tgc ttc gagggg aga gag aat gct gca gtt tgg aaa 2658 Thr Val Ala His Cys Phe Glu GlyArg Glu Asn Ala Ala Val Trp Lys 840 845 850 855 gtg gtg ctt ggc atc aacaat cta gac cat cca tca gtg ttc atg cag 2706 Val Val Leu Gly Ile Asn AsnLeu Asp His Pro Ser Val Phe Met Gln 860 865 870 aca cgc ttt gtg aag accatc atc ctg cat ccc cgc tac agt cga gca 2754 Thr Arg Phe Val Lys Thr IleIle Leu His Pro Arg Tyr Ser Arg Ala 875 880 885 gtg gtg gac tat gac atcagc atc gtt gag ctg agt gaa gac atc agt 2802 Val Val Asp Tyr Asp Ile SerIle Val Glu Leu Ser Glu Asp Ile Ser 890 895 900 gag act ggc tac gtc cggcct gtc tgc ttg ccc aac ccg gag cag tgg 2850 Glu Thr Gly Tyr Val Arg ProVal Cys Leu Pro Asn Pro Glu Gln Trp 905 910 915 cta gag cct gac acg tactgc tat atc aca ggc tgg ggc cac atg ggc 2898 Leu Glu Pro Asp Thr Tyr CysTyr Ile Thr Gly Trp Gly His Met Gly 920 925 930 935 aat aaa atg cca tttaag ctg caa gag gga gag gtc cgc att att tct 2946 Asn Lys Met Pro Phe LysLeu Gln Glu Gly Glu Val Arg Ile Ile Ser 940 945 950 ctg gaa cat tgt cagtcc tac ttt gac atg aag acc atc acc act cgg 2994 Leu Glu His Cys Gln SerTyr Phe Asp Met Lys Thr Ile Thr Thr Arg 955 960 965 atg ata tgt gct ggctat gag tct ggc aca gtt gat tca tgc atg ggt 3042 Met Ile Cys Ala Gly TyrGlu Ser Gly Thr Val Asp Ser Cys Met Gly 970 975 980 gac agc ggt ggg cctctt gtt tgt gag aag cct gga gga cgg tgg aca 3090 Asp Ser Gly Gly Pro LeuVal Cys Glu Lys Pro Gly Gly Arg Trp Thr 985 990 995 tta ttt gga tta acttca tgg ggc tcc gtc tgc ttt tcc aaa gtc ctg 3138 Leu Phe Gly Leu Thr SerTrp Gly Ser Val Cys Phe Ser Lys Val Leu 1000 1005 1010 1015 ggg cct ggcgtt tat agt aat gtg tca tat ttc gtc gaa tgg att aaa 3186 Gly Pro Gly ValTyr Ser Asn Val Ser Tyr Phe Val Glu Trp Ile Lys 1020 1025 1030 aga cagatt tac atc cag acc ttt ctc cta aac taa ttataaggat 3232 Arg Gln Ile TyrIle Gln Thr Phe Leu Leu Asn * 1035 1040 gatcagagac ttttgccagc tacactaaaagaaaatggcc ttcttgactg tgaagagctg 3292 cctgcagaga gctgtacaga agcacttttcatggacagaa atgctcaatc gtgcactgca 3352 aatttgcatg tttgttttgg actaatttttttcaatttat tttttcacct tcatttttct 3412 cttatttcaa gttcaatgaa agactttacaaaagcaaaca aagcagactt tgtccttttg 3472 ccaggcctaa ccatgactgc agcacaaaattatcgactct ggcgagattt aaaatcaggt 3532 gctacagtaa caggttatgg aatggtctcttttatcctat cacaaaaaaa gacatagata 3592 tttaggctga ttaattatct ctaccagtttttgtttctca agctcagtgc atagtggtaa 3652 atttcagtgt taacattgga gacttgcttttctttttctt tttttatacc ccacaattct 3712 tttttattac acttcgaatt ttagggtacacgagcacaac gtgcaggtta gttacatatg 3772 tatacatgtg ccatgttggt gtgctgaacccagtaactcg tcatttgatt tattaaaagc 3832 caagataatt tacatgttta aagtatttactattaccccc ttctaatgtt tgcataattc 3892 tgagaactga taaaagacag caataaaagaccagtgtcat ccatttaggt agcaagacat 3952 attgaatgca aagttcttta gatatcaatattaacacttg acattattgg accccccatt 4012 ctggatgtat atcaagatca taattttatagaagagtctc tatagaactg tcctcatagc 4072 tgggtttgtt caggatatat gagttggctgattgagactg caacaactac atctatattt 4132 atgggcaata ttttgtttta cttatgtggcaaagaactgg atattaaact ttgcaaaaga 4192 gaatttagat gagagatgca attttttaaaaagaaaatta atttgcatcc ctcgtttaat 4252 taaatttatt tttcagtttt cttgcgttcatccataccaa caaagtcata aagagcatat 4312 tttagagcac agtaagactt tgcatggagtaaaacatttt gtaattttcc tcaaaagatg 4372 tttaatatct ggtttcttct cattggtaattaaaatttta gaaatgattt ttagctctag 4432 gccactttac gcaactcaat ttctgaagcaattagtggta aaaagtattt ttccccacta 4492 aaaaacttta aaacacaaat cttcatatatacttaattta attagtcagg catccatttt 4552 gccttttaaa caactaggat tccctactaacctccaccag caacctggac tgcctcagca 4612 ttccaaatag atactacctg caattttatacatgtatttt tgtatctttt ctgtgtgtaa 4672 acatagttga aattcaaaaa gttgtagcaatttctatact attcatctcc tgtccttcag 4732 tttgtataaa cctaaggaga gtgtgaaatccagcaactga attgtggtca cgattgtatg 4792 aaagttcaag aacatatgtc agttttgttacagttgtagc tacatactca atgtatcaac 4852 ttttagcctg ctcaacttag gctcagtgaaatatatatat tatacttatt ttaaataatt 4912 cttaatacaa ataaaatggt a 4933 <210>SEQ ID NO 29 <211> LENGTH: 1042 <212> TYPE: PRT <213> ORGANISM: HomoSapien <400> SEQUENCE: 29 Met Lys Gln Ser Pro Ala Leu Ala Pro Glu GluArg Tyr Arg Arg Ala 1 5 10 15 Gly Ser Pro Lys Pro Val Leu Arg Ala AspAsp Asn Asn Met Gly Asn 20 25 30 Gly Cys Ser Gln Lys Leu Ala Thr Ala AsnLeu Leu Arg Phe Leu Leu 35 40 45 Leu Val Leu Ile Pro Cys Ile Cys Ala LeuVal Leu Leu Leu Val Ile 50 55 60 Leu Leu Ser Tyr Val Gly Thr Leu Gln LysVal Tyr Phe Lys Ser Asn 65 70 75 80 Gly Ser Glu Pro Leu Val Thr Asp GlyGlu Ile Gln Gly Ser Asp Val 85 90 95 Ile Leu Thr Asn Thr Ile Tyr Asn GlnSer Thr Val Val Ser Thr Ala 100 105 110 His Pro Asp Gln His Val Pro AlaTrp Thr Thr Asp Ala Ser Leu Pro 115 120 125 Gly Asp Gln Ser His Arg AsnThr Ser Ala Cys Met Asn Ile Thr His 130 135 140 Ser Gln Cys Gln Met LeuPro Tyr His Ala Thr Leu Thr Pro Leu Leu 145 150 155 160 Ser Val Val ArgAsn Met Glu Met Glu Lys Phe Leu Lys Phe Phe Thr 165 170 175 Tyr Leu HisArg Leu Ser Cys Tyr Gln His Ile Met Leu Phe Gly Cys 180 185 190 Thr LeuAla Phe Pro Glu Cys Ile Ile Asp Gly Asp Asp Ser His Gly 195 200 205 LeuLeu Pro Cys Arg Ser Phe Cys Glu Ala Ala Lys Glu Gly Cys Glu 210 215 220Ser Val Leu Gly Met Val Asn Tyr Ser Trp Pro Asp Phe Leu Arg Cys 225 230235 240 Ser Gln Phe Arg Asn Gln Thr Glu Ser Ser Asn Val Ser Arg Ile Cys245 250 255 Phe Ser Pro Gln Gln Glu Asn Gly Lys Gln Leu Leu Cys Gly ArgGly 260 265 270 Glu Asn Phe Leu Cys Ala Ser Gly Ile Cys Ile Pro Gly LysLeu Gln 275 280 285 Cys Asn Gly Tyr Asn Asp Cys Asp Asp Trp Ser Asp GluAla His Cys 290 295 300 Asn Cys Ser Glu Asn Leu Phe His Cys His Thr GlyLys Cys Leu Asn 305 310 315 320 Tyr Ser Leu Val Cys Asp Gly Tyr Asp AspCys Gly Asp Leu Ser Asp 325 330 335 Glu Gln Asn Cys Asp Cys Asn Pro ThrThr Glu His Arg Cys Gly Asp 340 345 350 Gly Arg Cys Ile Ala Met Glu TrpVal Cys Asp Gly Asp His Asp Cys 355 360 365 Val Asp Lys Ser Asp Glu ValAsn Cys Ser Cys His Ser Gln Gly Leu 370 375 380 Val Glu Cys Arg Asn GlyGln Cys Ile Pro Ser Thr Phe Gln Cys Asp 385 390 395 400 Gly Asp Glu AspCys Lys Asp Gly Ser Asp Glu Glu Asn Cys Ser Val 405 410 415 Ile Gln ThrSer Cys Gln Glu Gly Asp Gln Arg Cys Leu Tyr Asn Pro 420 425 430 Cys LeuAsp Ser Cys Gly Gly Ser Ser Leu Cys Asp Pro Asn Asn Ser 435 440 445 LeuAsn Asn Cys Ser Gln Cys Glu Pro Ile Thr Leu Glu Leu Cys Met 450 455 460Asn Leu Pro Tyr Asn Ser Thr Ser Tyr Pro Asn Tyr Phe Gly His Arg 465 470475 480 Thr Gln Lys Glu Ala Ser Ile Ser Trp Glu Ser Ser Leu Phe Pro Ala485 490 495 Leu Val Gln Thr Asn Cys Tyr Lys Tyr Leu Met Phe Phe Ser CysThr 500 505 510 Ile Leu Val Pro Lys Cys Asp Val Asn Thr Gly Glu Arg IlePro Pro 515 520 525 Cys Arg Ala Leu Cys Glu His Ser Lys Glu Arg Cys GluSer Val Leu 530 535 540 Gly Ile Val Gly Leu Gln Trp Pro Glu Asp Thr AspCys Ser Gln Phe 545 550 555 560 Pro Glu Glu Asn Ser Asp Asn Gln Thr CysLeu Met Pro Asp Glu Tyr 565 570 575 Val Glu Glu Cys Ser Pro Ser His PheLys Cys Arg Ser Gly Gln Cys 580 585 590 Val Leu Ala Ser Arg Arg Cys AspGly Gln Ala Asp Cys Asp Asp Asp 595 600 605 Ser Asp Glu Glu Asn Cys GlyCys Lys Glu Arg Asp Leu Trp Glu Cys 610 615 620 Pro Ser Asn Lys Gln CysLeu Lys His Thr Val Ile Cys Asp Gly Phe 625 630 635 640 Pro Asp Cys ProAsp Tyr Met Asp Glu Lys Asn Cys Ser Phe Cys Gln 645 650 655 Asp Asp GluLeu Glu Cys Ala Asn His Ala Cys Val Ser Arg Asp Leu 660 665 670 Trp CysAsp Gly Glu Ala Asp Cys Ser Asp Ser Ser Asp Glu Trp Asp 675 680 685 CysVal Thr Leu Ser Ile Asn Val Asn Ser Ser Ser Phe Leu Met Val 690 695 700His Arg Ala Ala Thr Glu His His Val Cys Ala Asp Gly Trp Gln Glu 705 710715 720 Ile Leu Ser Gln Leu Ala Cys Lys Gln Met Gly Leu Gly Glu Pro Ser725 730 735 Val Thr Lys Leu Ile Gln Glu Gln Glu Lys Glu Pro Arg Trp LeuThr 740 745 750 Leu His Ser Asn Trp Glu Ser Leu Asn Gly Thr Thr Leu HisGlu Leu 755 760 765 Leu Val Asn Gly Gln Ser Cys Glu Ser Arg Ser Lys IleSer Leu Leu 770 775 780 Cys Thr Lys Gln Asp Cys Gly Arg Arg Pro Ala AlaArg Met Asn Lys 785 790 795 800 Arg Ile Leu Gly Gly Arg Thr Ser Arg ProGly Arg Trp Pro Trp Gln 805 810 815 Cys Ser Leu Gln Ser Glu Pro Ser GlyHis Ile Cys Gly Cys Val Leu 820 825 830 Ile Ala Lys Lys Trp Val Leu ThrVal Ala His Cys Phe Glu Gly Arg 835 840 845 Glu Asn Ala Ala Val Trp LysVal Val Leu Gly Ile Asn Asn Leu Asp 850 855 860 His Pro Ser Val Phe MetGln Thr Arg Phe Val Lys Thr Ile Ile Leu 865 870 875 880 His Pro Arg TyrSer Arg Ala Val Val Asp Tyr Asp Ile Ser Ile Val 885 890 895 Glu Leu SerGlu Asp Ile Ser Glu Thr Gly Tyr Val Arg Pro Val Cys 900 905 910 Leu ProAsn Pro Glu Gln Trp Leu Glu Pro Asp Thr Tyr Cys Tyr Ile 915 920 925 ThrGly Trp Gly His Met Gly Asn Lys Met Pro Phe Lys Leu Gln Glu 930 935 940Gly Glu Val Arg Ile Ile Ser Leu Glu His Cys Gln Ser Tyr Phe Asp 945 950955 960 Met Lys Thr Ile Thr Thr Arg Met Ile Cys Ala Gly Tyr Glu Ser Gly965 970 975 Thr Val Asp Ser Cys Met Gly Asp Ser Gly Gly Pro Leu Val CysGlu 980 985 990 Lys Pro Gly Gly Arg Trp Thr Leu Phe Gly Leu Thr Ser TrpGly Ser 995 1000 1005 Val Cys Phe Ser Lys Val Leu Gly Pro Gly Val TyrSer Asn Val Ser 1010 1015 1020 Tyr Phe Val Glu Trp Ile Lys Arg Gln IleTyr Ile Gln Thr Phe Leu 1025 1030 1035 1040 Leu Asn <210> SEQ ID NO 30<211> LENGTH: 3696 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (41)...(3100) <223> OTHERINFORMATION: Nucleic acid encoding human enterokinase <300> PUBLICATIONINFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank HSU09860 <309>DATABASE ENTRY DATE: 1995-06-03 <400> SEQUENCE: 30 accagacagt tcttaaattagcaagccttc aaaaccaaaa atg ggg tcg aaa aga 55 Met Gly Ser Lys Arg 1 5 ggcata tct tct agg cat cat tct ctc agc tcc tat gaa atc atg ttt 103 Gly IleSer Ser Arg His His Ser Leu Ser Ser Tyr Glu Ile Met Phe 10 15 20 gca gctctc ttt gcc ata ttg gta gtg ctc tgt gct gga tta att gca 151 Ala Ala LeuPhe Ala Ile Leu Val Val Leu Cys Ala Gly Leu Ile Ala 25 30 35 gta tcc tgcctg aca atc aag gaa tcc caa cga ggt gca gca ctt gga 199 Val Ser Cys LeuThr Ile Lys Glu Ser Gln Arg Gly Ala Ala Leu Gly 40 45 50 cag agt cat gaagcc aga gcg aca ttt aaa ata aca tcc gga gtt aca 247 Gln Ser His Glu AlaArg Ala Thr Phe Lys Ile Thr Ser Gly Val Thr 55 60 65 tat aat cct aat ttgcaa gac aaa ctc tca gtg gat ttc aaa gtt ctt 295 Tyr Asn Pro Asn Leu GlnAsp Lys Leu Ser Val Asp Phe Lys Val Leu 70 75 80 85 gct ttt gac ctt cagcaa atg ata gat gag atc ttt cta tca agc aat 343 Ala Phe Asp Leu Gln GlnMet Ile Asp Glu Ile Phe Leu Ser Ser Asn 90 95 100 ctg aag aat gaa tataag aac tca aga gtt tta caa ttt gaa aat ggc 391 Leu Lys Asn Glu Tyr LysAsn Ser Arg Val Leu Gln Phe Glu Asn Gly 105 110 115 agc att ata gtc gtattt gac ctt ttc ttt gcc cag tgg gtg tca gat 439 Ser Ile Ile Val Val PheAsp Leu Phe Phe Ala Gln Trp Val Ser Asp 120 125 130 caa aat gta aaa gaagaa ctg att caa ggc ctt gaa gca aat aaa tcc 487 Gln Asn Val Lys Glu GluLeu Ile Gln Gly Leu Glu Ala Asn Lys Ser 135 140 145 agc caa ctg gtc actttc cat att gat ttg aac agc gtt gat atc cta 535 Ser Gln Leu Val Thr PheHis Ile Asp Leu Asn Ser Val Asp Ile Leu 150 155 160 165 gac aag cta acaacc acc agt cat ctg gca act cca gga aat gtc tca 583 Asp Lys Leu Thr ThrThr Ser His Leu Ala Thr Pro Gly Asn Val Ser 170 175 180 ata gag tgc ctgcct ggt tca agt cct tgt act gat gct cta acg tgt 631 Ile Glu Cys Leu ProGly Ser Ser Pro Cys Thr Asp Ala Leu Thr Cys 185 190 195 ata aaa gct gattta ttt tgt gat gga gaa gta aac tgt cca gat ggt 679 Ile Lys Ala Asp LeuPhe Cys Asp Gly Glu Val Asn Cys Pro Asp Gly 200 205 210 tct gac gaa gacaat aaa atg tgt gcc aca gtt tgt gat gga aga ttt 727 Ser Asp Glu Asp AsnLys Met Cys Ala Thr Val Cys Asp Gly Arg Phe 215 220 225 ttg tta act ggatca tct ggg tct ttc cag gct act cat tat cca aaa 775 Leu Leu Thr Gly SerSer Gly Ser Phe Gln Ala Thr His Tyr Pro Lys 230 235 240 245 cct tct gaaaca agt gtt gtc tgc cag tgg atc ata cgt gta aac caa 823 Pro Ser Glu ThrSer Val Val Cys Gln Trp Ile Ile Arg Val Asn Gln 250 255 260 gga ctt tccatt aaa ctg agc ttc gat gat ttt aat aca tat tat aca 871 Gly Leu Ser IleLys Leu Ser Phe Asp Asp Phe Asn Thr Tyr Tyr Thr 265 270 275 gat ata ttagat att tat gaa ggt gta gga tca agc aag att tta aga 919 Asp Ile Leu AspIle Tyr Glu Gly Val Gly Ser Ser Lys Ile Leu Arg 280 285 290 gct tct atttgg gaa act aat cct ggc aca ata aga att ttt tcc aac 967 Ala Ser Ile TrpGlu Thr Asn Pro Gly Thr Ile Arg Ile Phe Ser Asn 295 300 305 caa gtt actgcc acc ttt ctt ata gaa tct gat gaa agt gat tat gtt 1015 Gln Val Thr AlaThr Phe Leu Ile Glu Ser Asp Glu Ser Asp Tyr Val 310 315 320 325 ggc tttaat gca aca tat act gca ttt aac agc agt gag ctt aat aat 1063 Gly Phe AsnAla Thr Tyr Thr Ala Phe Asn Ser Ser Glu Leu Asn Asn 330 335 340 tat gagaaa att aat tgt aac ttt gag gat ggc ttt tgt ttc tgg gtc 1111 Tyr Glu LysIle Asn Cys Asn Phe Glu Asp Gly Phe Cys Phe Trp Val 345 350 355 cag gatcta aat gat gat aat gaa tgg gaa agg att cag gga agc acc 1159 Gln Asp LeuAsn Asp Asp Asn Glu Trp Glu Arg Ile Gln Gly Ser Thr 360 365 370 ttt tctcct ttt act gga ccc aat ttt gac cac act ttt ggc aat gct 1207 Phe Ser ProPhe Thr Gly Pro Asn Phe Asp His Thr Phe Gly Asn Ala 375 380 385 tca ggattt tac att tct acc cca act gga cca gga ggg aga caa gaa 1255 Ser Gly PheTyr Ile Ser Thr Pro Thr Gly Pro Gly Gly Arg Gln Glu 390 395 400 405 cgagtg ggg ctt tta agc ctc cct ttg gac ccc act ttg gag cca gct 1303 Arg ValGly Leu Leu Ser Leu Pro Leu Asp Pro Thr Leu Glu Pro Ala 410 415 420 tgcctt agt ttc tgg tat cat atg tat ggt gaa aat gtc cat aaa tta 1351 Cys LeuSer Phe Trp Tyr His Met Tyr Gly Glu Asn Val His Lys Leu 425 430 435 agcatt aat atc agc aat gac caa aat atg gag aag aca gtt ttc caa 1399 Ser IleAsn Ile Ser Asn Asp Gln Asn Met Glu Lys Thr Val Phe Gln 440 445 450 aaggaa gga aat tat gga gac aat tgg aat tat gga caa gta acc cta 1447 Lys GluGly Asn Tyr Gly Asp Asn Trp Asn Tyr Gly Gln Val Thr Leu 455 460 465 aatgaa aca gtt aaa ttt aag gtt gct ttt aat gct ttt aaa aac aag 1495 Asn GluThr Val Lys Phe Lys Val Ala Phe Asn Ala Phe Lys Asn Lys 470 475 480 485atc ctg agt gat att gcg ttg gat gac att agc cta aca tat ggg att 1543 IleLeu Ser Asp Ile Ala Leu Asp Asp Ile Ser Leu Thr Tyr Gly Ile 490 495 500tgc aat ggg agt ctt tat cca gaa cca act ttg gtg cca act cct cca 1591 CysAsn Gly Ser Leu Tyr Pro Glu Pro Thr Leu Val Pro Thr Pro Pro 505 510 515cca gaa ctt cct acg gac tgt gga gga cct ttt gag ctg tgg gag cca 1639 ProGlu Leu Pro Thr Asp Cys Gly Gly Pro Phe Glu Leu Trp Glu Pro 520 525 530aat aca aca ttc agt tct acg aac ttt cca aac agc tac cct aat ctg 1687 AsnThr Thr Phe Ser Ser Thr Asn Phe Pro Asn Ser Tyr Pro Asn Leu 535 540 545gct ttc tgt gtt tgg att tta aat gca caa aaa gga aag aat ata caa 1735 AlaPhe Cys Val Trp Ile Leu Asn Ala Gln Lys Gly Lys Asn Ile Gln 550 555 560565 ctt cat ttt caa gaa ttt gac tta gaa aat att aac gat gta gtt gaa 1783Leu His Phe Gln Glu Phe Asp Leu Glu Asn Ile Asn Asp Val Val Glu 570 575580 ata aga gat ggt gaa gaa gct gat tcc ttg ctc tta gct gtg tac aca 1831Ile Arg Asp Gly Glu Glu Ala Asp Ser Leu Leu Leu Ala Val Tyr Thr 585 590595 ggg cct ggc cca gta aag gat gtg ttc tct acc acc aac aga atg act 1879Gly Pro Gly Pro Val Lys Asp Val Phe Ser Thr Thr Asn Arg Met Thr 600 605610 gtg ctt ctc atc act aac gat gtg ttg gca aga gga ggg ttt aaa gca 1927Val Leu Leu Ile Thr Asn Asp Val Leu Ala Arg Gly Gly Phe Lys Ala 615 620625 aac ttt act act ggc tat cac ttg ggg att cca gag cca tgc aag gca 1975Asn Phe Thr Thr Gly Tyr His Leu Gly Ile Pro Glu Pro Cys Lys Ala 630 635640 645 gac cat ttt caa tgt aaa aat gga gag tgt gtt cca ctg gtg aat ctc2023 Asp His Phe Gln Cys Lys Asn Gly Glu Cys Val Pro Leu Val Asn Leu 650655 660 tgt gac ggt cat ctg cac tgt gag gat ggc tca gat gaa gca gat tgt2071 Cys Asp Gly His Leu His Cys Glu Asp Gly Ser Asp Glu Ala Asp Cys 665670 675 gtg cgt ttt ttc aat ggc aca acg aac aac aat ggt tta gtg cgg ttc2119 Val Arg Phe Phe Asn Gly Thr Thr Asn Asn Asn Gly Leu Val Arg Phe 680685 690 aga atc cag agc ata tgg cat aca gct tgt gct gag aac tgg acc acc2167 Arg Ile Gln Ser Ile Trp His Thr Ala Cys Ala Glu Asn Trp Thr Thr 695700 705 cag att tca aat gat gtt tgt caa ctg ctg gga cta ggg agt gga aac2215 Gln Ile Ser Asn Asp Val Cys Gln Leu Leu Gly Leu Gly Ser Gly Asn 710715 720 725 tca tca aag cca atc ttc tct acc gat ggt gga cca ttt gtc aaatta 2263 Ser Ser Lys Pro Ile Phe Ser Thr Asp Gly Gly Pro Phe Val Lys Leu730 735 740 aac aca gca cct gat ggc cac tta ata cta aca ccc agt caa cagtgt 2311 Asn Thr Ala Pro Asp Gly His Leu Ile Leu Thr Pro Ser Gln Gln Cys745 750 755 tta cag gat tcc ttg att cgg tta cag tgt aac cat aaa tct tgtgga 2359 Leu Gln Asp Ser Leu Ile Arg Leu Gln Cys Asn His Lys Ser Cys Gly760 765 770 aaa aaa ctg gca gct caa gac atc acc cca aag att gtt gga ggaagt 2407 Lys Lys Leu Ala Ala Gln Asp Ile Thr Pro Lys Ile Val Gly Gly Ser775 780 785 aat gcc aaa gaa ggg gcc tgg ccc tgg gtt gtg ggt ctg tat tatggc 2455 Asn Ala Lys Glu Gly Ala Trp Pro Trp Val Val Gly Leu Tyr Tyr Gly790 795 800 805 ggc cga ctg ctc tgc ggc gca tct ctc gtc agc agt gac tggctg gtg 2503 Gly Arg Leu Leu Cys Gly Ala Ser Leu Val Ser Ser Asp Trp LeuVal 810 815 820 tcc gcc gca cac tgc gtg tat ggg aga aac tta gag cca tccaag tgg 2551 Ser Ala Ala His Cys Val Tyr Gly Arg Asn Leu Glu Pro Ser LysTrp 825 830 835 aca gca atc cta ggc ctg cat atg aaa tca aat ctg acc tctcct caa 2599 Thr Ala Ile Leu Gly Leu His Met Lys Ser Asn Leu Thr Ser ProGln 840 845 850 aca gtc cct cga tta ata gat gaa att gtc ata aac cct cattac aat 2647 Thr Val Pro Arg Leu Ile Asp Glu Ile Val Ile Asn Pro His TyrAsn 855 860 865 agg cga aga aag gac aac gac att gcc atg atg cat ctg gaattt aaa 2695 Arg Arg Arg Lys Asp Asn Asp Ile Ala Met Met His Leu Glu PheLys 870 875 880 885 gtg aat tac aca gat tac ata caa cct att tgt tta ccggaa gaa aat 2743 Val Asn Tyr Thr Asp Tyr Ile Gln Pro Ile Cys Leu Pro GluGlu Asn 890 895 900 caa gtt ttt cct cca gga aga aat tgt tct att gct ggttgg ggg acg 2791 Gln Val Phe Pro Pro Gly Arg Asn Cys Ser Ile Ala Gly TrpGly Thr 905 910 915 gtt gta tat caa ggt act act gca aac ata ttg caa gaagct gat gtt 2839 Val Val Tyr Gln Gly Thr Thr Ala Asn Ile Leu Gln Glu AlaAsp Val 920 925 930 cct ctt cta tca aat gag aga tgc caa cag cag atg ccagaa tat aac 2887 Pro Leu Leu Ser Asn Glu Arg Cys Gln Gln Gln Met Pro GluTyr Asn 935 940 945 att act gaa aat atg ata tgt gca ggc tat gaa gaa ggagga ata gat 2935 Ile Thr Glu Asn Met Ile Cys Ala Gly Tyr Glu Glu Gly GlyIle Asp 950 955 960 965 tct tgt cag ggg gat tca gga gga cca tta atg tgccaa gaa aac aac 2983 Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Met Cys GlnGlu Asn Asn 970 975 980 agg tgg ttc ctt gct ggt gtg acc tca ttt gga tacaag tgt gcc ctg 3031 Arg Trp Phe Leu Ala Gly Val Thr Ser Phe Gly Tyr LysCys Ala Leu 985 990 995 cct aat cgc ccc gga gtg tat gcc agg gtc tca aggttt acc gaa tgg 3079 Pro Asn Arg Pro Gly Val Tyr Ala Arg Val Ser Arg PheThr Glu Trp 1000 1005 1010 ata caa agt ttt cta cat tag cgcatttcttaaactaaaca ggaaagtcgc 3130 Ile Gln Ser Phe Leu His * 1015 attattttcccattctactc tagaaagcat ggaaattaag tgtttcgtac aaaaatttta 3190 aaaagttaccaaaggttttt attcttacct atgtcaatga aatgctaggg ggccagggaa 3250 acaaaattttaaaaataata aaattcacca tagcaataca gaataacttt aaaataccat 3310 taaatacatttgtatttcat tgtgaacagg tatttcttca cagatctcat ttttaaaatt 3370 cttaatgattatttttatta cttactgttg tttaaaggga tgttatttta aagcatatac 3430 catacacttaagaaatttga gcagaattta aaaaagaaag aaaataaatt gtttttccca 3490 aagtatgtcactgttggaaa taaactgcca taaattttct agttccagtt tagtttgctg 3550 ctattagcagaaactcaatt gtttctctgt cttttctatc aaaattttca acatatgcat 3610 aaccttagtattttcccaac caatagaaac tatttattgt aagcttatgt cacaggcctg 3670 gactaaattgattttacgtt cctctt 3696 <210> SEQ ID NO 31 <211> LENGTH: 1019 <212> TYPE:PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 31 Met Gly Ser Lys ArgGly Ile Ser Ser Arg His His Ser Leu Ser Ser 1 5 10 15 Tyr Glu Ile MetPhe Ala Ala Leu Phe Ala Ile Leu Val Val Leu Cys 20 25 30 Ala Gly Leu IleAla Val Ser Cys Leu Thr Ile Lys Glu Ser Gln Arg 35 40 45 Gly Ala Ala LeuGly Gln Ser His Glu Ala Arg Ala Thr Phe Lys Ile 50 55 60 Thr Ser Gly ValThr Tyr Asn Pro Asn Leu Gln Asp Lys Leu Ser Val 65 70 75 80 Asp Phe LysVal Leu Ala Phe Asp Leu Gln Gln Met Ile Asp Glu Ile 85 90 95 Phe Leu SerSer Asn Leu Lys Asn Glu Tyr Lys Asn Ser Arg Val Leu 100 105 110 Gln PheGlu Asn Gly Ser Ile Ile Val Val Phe Asp Leu Phe Phe Ala 115 120 125 GlnTrp Val Ser Asp Gln Asn Val Lys Glu Glu Leu Ile Gln Gly Leu 130 135 140Glu Ala Asn Lys Ser Ser Gln Leu Val Thr Phe His Ile Asp Leu Asn 145 150155 160 Ser Val Asp Ile Leu Asp Lys Leu Thr Thr Thr Ser His Leu Ala Thr165 170 175 Pro Gly Asn Val Ser Ile Glu Cys Leu Pro Gly Ser Ser Pro CysThr 180 185 190 Asp Ala Leu Thr Cys Ile Lys Ala Asp Leu Phe Cys Asp GlyGlu Val 195 200 205 Asn Cys Pro Asp Gly Ser Asp Glu Asp Asn Lys Met CysAla Thr Val 210 215 220 Cys Asp Gly Arg Phe Leu Leu Thr Gly Ser Ser GlySer Phe Gln Ala 225 230 235 240 Thr His Tyr Pro Lys Pro Ser Glu Thr SerVal Val Cys Gln Trp Ile 245 250 255 Ile Arg Val Asn Gln Gly Leu Ser IleLys Leu Ser Phe Asp Asp Phe 260 265 270 Asn Thr Tyr Tyr Thr Asp Ile LeuAsp Ile Tyr Glu Gly Val Gly Ser 275 280 285 Ser Lys Ile Leu Arg Ala SerIle Trp Glu Thr Asn Pro Gly Thr Ile 290 295 300 Arg Ile Phe Ser Asn GlnVal Thr Ala Thr Phe Leu Ile Glu Ser Asp 305 310 315 320 Glu Ser Asp TyrVal Gly Phe Asn Ala Thr Tyr Thr Ala Phe Asn Ser 325 330 335 Ser Glu LeuAsn Asn Tyr Glu Lys Ile Asn Cys Asn Phe Glu Asp Gly 340 345 350 Phe CysPhe Trp Val Gln Asp Leu Asn Asp Asp Asn Glu Trp Glu Arg 355 360 365 IleGln Gly Ser Thr Phe Ser Pro Phe Thr Gly Pro Asn Phe Asp His 370 375 380Thr Phe Gly Asn Ala Ser Gly Phe Tyr Ile Ser Thr Pro Thr Gly Pro 385 390395 400 Gly Gly Arg Gln Glu Arg Val Gly Leu Leu Ser Leu Pro Leu Asp Pro405 410 415 Thr Leu Glu Pro Ala Cys Leu Ser Phe Trp Tyr His Met Tyr GlyGlu 420 425 430 Asn Val His Lys Leu Ser Ile Asn Ile Ser Asn Asp Gln AsnMet Glu 435 440 445 Lys Thr Val Phe Gln Lys Glu Gly Asn Tyr Gly Asp AsnTrp Asn Tyr 450 455 460 Gly Gln Val Thr Leu Asn Glu Thr Val Lys Phe LysVal Ala Phe Asn 465 470 475 480 Ala Phe Lys Asn Lys Ile Leu Ser Asp IleAla Leu Asp Asp Ile Ser 485 490 495 Leu Thr Tyr Gly Ile Cys Asn Gly SerLeu Tyr Pro Glu Pro Thr Leu 500 505 510 Val Pro Thr Pro Pro Pro Glu LeuPro Thr Asp Cys Gly Gly Pro Phe 515 520 525 Glu Leu Trp Glu Pro Asn ThrThr Phe Ser Ser Thr Asn Phe Pro Asn 530 535 540 Ser Tyr Pro Asn Leu AlaPhe Cys Val Trp Ile Leu Asn Ala Gln Lys 545 550 555 560 Gly Lys Asn IleGln Leu His Phe Gln Glu Phe Asp Leu Glu Asn Ile 565 570 575 Asn Asp ValVal Glu Ile Arg Asp Gly Glu Glu Ala Asp Ser Leu Leu 580 585 590 Leu AlaVal Tyr Thr Gly Pro Gly Pro Val Lys Asp Val Phe Ser Thr 595 600 605 ThrAsn Arg Met Thr Val Leu Leu Ile Thr Asn Asp Val Leu Ala Arg 610 615 620Gly Gly Phe Lys Ala Asn Phe Thr Thr Gly Tyr His Leu Gly Ile Pro 625 630635 640 Glu Pro Cys Lys Ala Asp His Phe Gln Cys Lys Asn Gly Glu Cys Val645 650 655 Pro Leu Val Asn Leu Cys Asp Gly His Leu His Cys Glu Asp GlySer 660 665 670 Asp Glu Ala Asp Cys Val Arg Phe Phe Asn Gly Thr Thr AsnAsn Asn 675 680 685 Gly Leu Val Arg Phe Arg Ile Gln Ser Ile Trp His ThrAla Cys Ala 690 695 700 Glu Asn Trp Thr Thr Gln Ile Ser Asn Asp Val CysGln Leu Leu Gly 705 710 715 720 Leu Gly Ser Gly Asn Ser Ser Lys Pro IlePhe Ser Thr Asp Gly Gly 725 730 735 Pro Phe Val Lys Leu Asn Thr Ala ProAsp Gly His Leu Ile Leu Thr 740 745 750 Pro Ser Gln Gln Cys Leu Gln AspSer Leu Ile Arg Leu Gln Cys Asn 755 760 765 His Lys Ser Cys Gly Lys LysLeu Ala Ala Gln Asp Ile Thr Pro Lys 770 775 780 Ile Val Gly Gly Ser AsnAla Lys Glu Gly Ala Trp Pro Trp Val Val 785 790 795 800 Gly Leu Tyr TyrGly Gly Arg Leu Leu Cys Gly Ala Ser Leu Val Ser 805 810 815 Ser Asp TrpLeu Val Ser Ala Ala His Cys Val Tyr Gly Arg Asn Leu 820 825 830 Glu ProSer Lys Trp Thr Ala Ile Leu Gly Leu His Met Lys Ser Asn 835 840 845 LeuThr Ser Pro Gln Thr Val Pro Arg Leu Ile Asp Glu Ile Val Ile 850 855 860Asn Pro His Tyr Asn Arg Arg Arg Lys Asp Asn Asp Ile Ala Met Met 865 870875 880 His Leu Glu Phe Lys Val Asn Tyr Thr Asp Tyr Ile Gln Pro Ile Cys885 890 895 Leu Pro Glu Glu Asn Gln Val Phe Pro Pro Gly Arg Asn Cys SerIle 900 905 910 Ala Gly Trp Gly Thr Val Val Tyr Gln Gly Thr Thr Ala AsnIle Leu 915 920 925 Gln Glu Ala Asp Val Pro Leu Leu Ser Asn Glu Arg CysGln Gln Gln 930 935 940 Met Pro Glu Tyr Asn Ile Thr Glu Asn Met Ile CysAla Gly Tyr Glu 945 950 955 960 Glu Gly Gly Ile Asp Ser Cys Gln Gly AspSer Gly Gly Pro Leu Met 965 970 975 Cys Gln Glu Asn Asn Arg Trp Phe LeuAla Gly Val Thr Ser Phe Gly 980 985 990 Tyr Lys Cys Ala Leu Pro Asn ArgPro Gly Val Tyr Ala Arg Val Ser 995 1000 1005 Arg Phe Thr Glu Trp IleGln Ser Phe Leu His 1010 1015 <210> SEQ ID NO 32 <211> LENGTH: 1500<212> TYPE: DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221>NAME/KEY: CDS <222> LOCATION: (62)...(1318) <223> OTHER INFORMATION:Nucleotide sequence encoding human airway trypsin-like protease <300>PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBankAB002134 <309> DATABASE ENTRY DATE: 1998-06-04 <400> SEQUENCE: 32gagtgggaat ctcaaagcag ttgagtaggc agaaaaaaga acctcttcat taaggattaa 60 aatg tat agg cca gca cgt gta act tcg act tca aga ttt ctg aat cca 109 MetTyr Arg Pro Ala Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro 1 5 10 15tat gta gta tgt ttc att gtc gtc gca ggg gta gtg atc ctg gca gtc 157 TyrVal Val Cys Phe Ile Val Val Ala Gly Val Val Ile Leu Ala Val 20 25 30 accata gct cta ctt gtt tac ttt tta gct ttt gat caa aaa tct tac 205 Thr IleAla Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr 35 40 45 ttt tatagg agc agt ttt caa ctc cta aat gtt gaa tat aat agt cag 253 Phe Tyr ArgSer Ser Phe Gln Leu Leu Asn Val Glu Tyr Asn Ser Gln 50 55 60 tta aat tcacca gct aca cag gaa tac agg act ttg agt gga aga att 301 Leu Asn Ser ProAla Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile 65 70 75 80 gaa tct ctgatt act aaa aca ttc aaa gaa tca aat tta aga aat cag 349 Glu Ser Leu IleThr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln 85 90 95 ttc atc aga gctcat gtt gcc aaa ctg agg caa gat ggt agt ggt gtg 397 Phe Ile Arg Ala HisVal Ala Lys Leu Arg Gln Asp Gly Ser Gly Val 100 105 110 aga gcg gat gttgtc atg aaa ttt caa ttc act aga aat aac aat gga 445 Arg Ala Asp Val ValMet Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly 115 120 125 gca tca atg aaaagc aga att gag tct gtt tta cga caa atg ctg aat 493 Ala Ser Met Lys SerArg Ile Glu Ser Val Leu Arg Gln Met Leu Asn 130 135 140 aac tct gga aacctg gaa ata aac cct tca act gag ata aca tca ctt 541 Asn Ser Gly Asn LeuGlu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu 145 150 155 160 act gac caggct gca gca aat tgg ctt att aat gaa tgt ggg gcc ggt 589 Thr Asp Gln AlaAla Ala Asn Trp Leu Ile Asn Glu Cys Gly Ala Gly 165 170 175 cca gac ctaata aca ttg tct gag cag aga atc ctt gga ggc act gag 637 Pro Asp Leu IleThr Leu Ser Glu Gln Arg Ile Leu Gly Gly Thr Glu 180 185 190 gct gag gaggga agc tgg ccg tgg caa gtc agt ctg cgg ctc aat aat 685 Ala Glu Glu GlySer Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn 195 200 205 gcc cac cactgt gga ggc agc ctg atc aat aac atg tgg atc ctg aca 733 Ala His His CysGly Gly Ser Leu Ile Asn Asn Met Trp Ile Leu Thr 210 215 220 gca gct cactgc ttc aga agc aac tct aat cct cgt gac tgg att gcc 781 Ala Ala His CysPhe Arg Ser Asn Ser Asn Pro Arg Asp Trp Ile Ala 225 230 235 240 acg tctggt att tcc aca aca ttt cct aaa cta aga atg aga gta aga 829 Thr Ser GlyIle Ser Thr Thr Phe Pro Lys Leu Arg Met Arg Val Arg 245 250 255 aat atttta att cat aac aat tat aaa tct gca act cat gaa aat gac 877 Asn Ile LeuIle His Asn Asn Tyr Lys Ser Ala Thr His Glu Asn Asp 260 265 270 att gcactt gtg aga ctt gag aac agt gtc acc ttt acc aaa gat atc 925 Ile Ala LeuVal Arg Leu Glu Asn Ser Val Thr Phe Thr Lys Asp Ile 275 280 285 cat agtgtg tgt ctc cca gct gct acc cag aat att cca cct ggc tct 973 His Ser ValCys Leu Pro Ala Ala Thr Gln Asn Ile Pro Pro Gly Ser 290 295 300 act gcttat gta aca gga tgg ggc gct caa gaa tat gct ggc cac aca 1021 Thr Ala TyrVal Thr Gly Trp Gly Ala Gln Glu Tyr Ala Gly His Thr 305 310 315 320 gttcca gag cta agg caa gga cag gtc aga ata ata agt aat gat gta 1069 Val ProGlu Leu Arg Gln Gly Gln Val Arg Ile Ile Ser Asn Asp Val 325 330 335 tgtaat gca cca cat agt tat aat gga gcc atc ttg tct gga atg ctg 1117 Cys AsnAla Pro His Ser Tyr Asn Gly Ala Ile Leu Ser Gly Met Leu 340 345 350 tgtgct gga gta cct caa ggt gga gtg gac gca tgt cag ggt gac tct 1165 Cys AlaGly Val Pro Gln Gly Gly Val Asp Ala Cys Gln Gly Asp Ser 355 360 365 ggtggc cca cta gta caa gaa gac tca cgg cgg ctt tgg ttt att gtg 1213 Gly GlyPro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val 370 375 380 gggata gta agc tgg gga gat cag tgt ggc ctg ccg gat aag cca gga 1261 Gly IleVal Ser Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly 385 390 395 400gtg tat act cga gtg aca gcc tac ctt gac tgg att agg caa caa act 1309 ValTyr Thr Arg Val Thr Ala Tyr Leu Asp Trp Ile Arg Gln Gln Thr 405 410 415ggg atc tag tgcaacaagt gcatccctgt tgcaaagtct gtatgcaggt 1358 Gly Ile *gtgcctgtct taaattccaa agctttacat ttcaactgaa aaagaaacta gaaatgtcct 1418aatttaacat cttgttacat aaatatggtt taacaaacac tgtttaacct ttctttatta 1478ttaaaggttt tctattttct cc 1500 <210> SEQ ID NO 33 <211> LENGTH: 418 <212>TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 33 Met Tyr Arg ProAla Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro 1 5 10 15 Tyr Val ValCys Phe Ile Val Val Ala Gly Val Val Ile Leu Ala Val 20 25 30 Thr Ile AlaLeu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr 35 40 45 Phe Tyr ArgSer Ser Phe Gln Leu Leu Asn Val Glu Tyr Asn Ser Gln 50 55 60 Leu Asn SerPro Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile 65 70 75 80 Glu SerLeu Ile Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln 85 90 95 Phe IleArg Ala His Val Ala Lys Leu Arg Gln Asp Gly Ser Gly Val 100 105 110 ArgAla Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly 115 120 125Ala Ser Met Lys Ser Arg Ile Glu Ser Val Leu Arg Gln Met Leu Asn 130 135140 Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu 145150 155 160 Thr Asp Gln Ala Ala Ala Asn Trp Leu Ile Asn Glu Cys Gly AlaGly 165 170 175 Pro Asp Leu Ile Thr Leu Ser Glu Gln Arg Ile Leu Gly GlyThr Glu 180 185 190 Ala Glu Glu Gly Ser Trp Pro Trp Gln Val Ser Leu ArgLeu Asn Asn 195 200 205 Ala His His Cys Gly Gly Ser Leu Ile Asn Asn MetTrp Ile Leu Thr 210 215 220 Ala Ala His Cys Phe Arg Ser Asn Ser Asn ProArg Asp Trp Ile Ala 225 230 235 240 Thr Ser Gly Ile Ser Thr Thr Phe ProLys Leu Arg Met Arg Val Arg 245 250 255 Asn Ile Leu Ile His Asn Asn TyrLys Ser Ala Thr His Glu Asn Asp 260 265 270 Ile Ala Leu Val Arg Leu GluAsn Ser Val Thr Phe Thr Lys Asp Ile 275 280 285 His Ser Val Cys Leu ProAla Ala Thr Gln Asn Ile Pro Pro Gly Ser 290 295 300 Thr Ala Tyr Val ThrGly Trp Gly Ala Gln Glu Tyr Ala Gly His Thr 305 310 315 320 Val Pro GluLeu Arg Gln Gly Gln Val Arg Ile Ile Ser Asn Asp Val 325 330 335 Cys AsnAla Pro His Ser Tyr Asn Gly Ala Ile Leu Ser Gly Met Leu 340 345 350 CysAla Gly Val Pro Gln Gly Gly Val Asp Ala Cys Gln Gly Asp Ser 355 360 365Gly Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val 370 375380 Gly Ile Val Ser Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly 385390 395 400 Val Tyr Thr Arg Val Thr Ala Tyr Leu Asp Trp Ile Arg Gln GlnThr 405 410 415 Gly Ile <210> SEQ ID NO 34 <211> LENGTH: 1783 <212>TYPE: DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (246)...(1499) <223> OTHER INFORMATION: Nucleic acidencoding human hepsin <300> PUBLICATION INFORMATION: <308> DATABASEACCESSION NUMBER: GenBank M18930 <309> DATABASE ENTRY DATE: 1993-06-11<400> SEQUENCE: 34 tcgagcccgc tttccaggga ccctacctga gggcccacaggtgaggcagc ctggcctagc 60 aggccccacg ccaccgcctc tgcctccagg ccgcccgctgctgcggggcc accatgctcc 120 tgcccaggcc tggagactga cccgaccccg gcactacctcgaggctccgc ccccacctgc 180 tggaccccag ggtcccaccc tggcccagga ggtcagccagggaatcatta acaagaggca 240 gtgac atg gcg cag aag gag ggt ggc cgg act gtgcca tgc tgc tcc aga 290 Met Ala Gln Lys Glu Gly Gly Arg Thr Val Pro CysCys Ser Arg 1 5 10 15 ccc aag gtg gca gct ctc act gcg ggg acc ctg ctactt ctg aca gcc 338 Pro Lys Val Ala Ala Leu Thr Ala Gly Thr Leu Leu LeuLeu Thr Ala 20 25 30 atc ggg gcg gca tcc tgg gcc att gtg gct gtt ctc ctcagg agt gac 386 Ile Gly Ala Ala Ser Trp Ala Ile Val Ala Val Leu Leu ArgSer Asp 35 40 45 cag gag ccg ctg tac cca gtg cag gtc agc tct gcg gac gctcgg ctc 434 Gln Glu Pro Leu Tyr Pro Val Gln Val Ser Ser Ala Asp Ala ArgLeu 50 55 60 atg gtc ttt gac aag acg gaa ggg acg tgg cgg ctg ctg tgc tcctcg 482 Met Val Phe Asp Lys Thr Glu Gly Thr Trp Arg Leu Leu Cys Ser Ser65 70 75 cgc tcc aac gcc agg gta gcc gga ctc agc tgc gag gag atg ggc ttc530 Arg Ser Asn Ala Arg Val Ala Gly Leu Ser Cys Glu Glu Met Gly Phe 8085 90 95 ctc agg gca ctg acc cac tcc gag ctg gac gtg cga acg gcg ggc gcc578 Leu Arg Ala Leu Thr His Ser Glu Leu Asp Val Arg Thr Ala Gly Ala 100105 110 aat ggc acg tcg ggc ttc ttc tgt gtg gac gag ggg agg ctg ccc cac626 Asn Gly Thr Ser Gly Phe Phe Cys Val Asp Glu Gly Arg Leu Pro His 115120 125 acc cag agg ctg ctg gag gtc atc tcc gtg tgt gat tgc ccc aga ggc674 Thr Gln Arg Leu Leu Glu Val Ile Ser Val Cys Asp Cys Pro Arg Gly 130135 140 cgt ttc ttg gcc gcc atc tgc caa gac tgt ggc cgc agg aag ctg ccc722 Arg Phe Leu Ala Ala Ile Cys Gln Asp Cys Gly Arg Arg Lys Leu Pro 145150 155 gtg gac cgc atc gtg gga ggc cgg gac acc agc ttg ggc cgg tgg ccg770 Val Asp Arg Ile Val Gly Gly Arg Asp Thr Ser Leu Gly Arg Trp Pro 160165 170 175 tgg caa gtc agc ctt cgc tat gat gga gca cac ctc tgt ggg ggatcc 818 Trp Gln Val Ser Leu Arg Tyr Asp Gly Ala His Leu Cys Gly Gly Ser180 185 190 ctg ctc tcc ggg gac tgg gtg ctg aca gcc gcc cac tgc ttc ccggag 866 Leu Leu Ser Gly Asp Trp Val Leu Thr Ala Ala His Cys Phe Pro Glu195 200 205 cgg aac cgg gtc ctg tcc cga tgg cga gtg ttt gcc ggt gcc gtggcc 914 Arg Asn Arg Val Leu Ser Arg Trp Arg Val Phe Ala Gly Ala Val Ala210 215 220 cag gcc tct ccc cac ggt ctg cag ctg ggg gtg cag gct gtg gtctac 962 Gln Ala Ser Pro His Gly Leu Gln Leu Gly Val Gln Ala Val Val Tyr225 230 235 cac ggg ggc tat ctt ccc ttt cgg gac ccc aac agc gag gag aacagc 1010 His Gly Gly Tyr Leu Pro Phe Arg Asp Pro Asn Ser Glu Glu Asn Ser240 245 250 255 aac gat att gcc ctg gtc cac ctc tcc agt ccc ctg ccc ctcaca gaa 1058 Asn Asp Ile Ala Leu Val His Leu Ser Ser Pro Leu Pro Leu ThrGlu 260 265 270 tac atc cag cct gtg tgc ctc cca gct gcc ggc cag gcc ctggtg gat 1106 Tyr Ile Gln Pro Val Cys Leu Pro Ala Ala Gly Gln Ala Leu ValAsp 275 280 285 ggc aag atc tgt acc gtg acg ggc tgg ggc aac acg cag tactat ggc 1154 Gly Lys Ile Cys Thr Val Thr Gly Trp Gly Asn Thr Gln Tyr TyrGly 290 295 300 caa cag gcc ggg gta ctc cag gag gct cga gtc ccc ata atcagc aat 1202 Gln Gln Ala Gly Val Leu Gln Glu Ala Arg Val Pro Ile Ile SerAsn 305 310 315 gat gtc tgc aat ggc gct gac ttc tat gga aac cag atc aagccc aag 1250 Asp Val Cys Asn Gly Ala Asp Phe Tyr Gly Asn Gln Ile Lys ProLys 320 325 330 335 atg ttc tgt gct ggc tac ccc gag ggt ggc att gat gcctgc cag ggc 1298 Met Phe Cys Ala Gly Tyr Pro Glu Gly Gly Ile Asp Ala CysGln Gly 340 345 350 gac agc ggt ggt ccc ttt gtg tgt gag gac agc atc tctcgg acg cca 1346 Asp Ser Gly Gly Pro Phe Val Cys Glu Asp Ser Ile Ser ArgThr Pro 355 360 365 cgt tgg cgg ctg tgt ggc att gtg agt tgg ggc act ggctgt gcc ctg 1394 Arg Trp Arg Leu Cys Gly Ile Val Ser Trp Gly Thr Gly CysAla Leu 370 375 380 gcc cag aag cca ggc gtc tac acc aaa gtc agt gac ttccgg gag tgg 1442 Ala Gln Lys Pro Gly Val Tyr Thr Lys Val Ser Asp Phe ArgGlu Trp 385 390 395 atc ttc cag gcc ata aag act cac tcc gaa gcc agc ggcatg gtg acc 1490 Ile Phe Gln Ala Ile Lys Thr His Ser Glu Ala Ser Gly MetVal Thr 400 405 410 415 cag ctc tga ccggtggctt ctcgctgcgc agcctccagggcccgaggtg 1539 Gln Leu * atcccggtgg tgggatccac gctgggccga ggatgggacgtttttcttct tgggcccggt 1599 ccacaggtcc aaggacaccc tccctccagg gtcctctcttccacagtggc gggcccactc 1659 agccccgaga ccacccaacc tcaccctcct gacccccatgtaaatattgt tctgctgtct 1719 gggactcctg tctaggtgcc cctgatgatg ggatgctctttaaataataa agatggtttt 1779 gatt 1783 <210> SEQ ID NO 35 <211> LENGTH:417 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 35 MetAla Gln Lys Glu Gly Gly Arg Thr Val Pro Cys Cys Ser Arg Pro 1 5 10 15Lys Val Ala Ala Leu Thr Ala Gly Thr Leu Leu Leu Leu Thr Ala Ile 20 25 30Gly Ala Ala Ser Trp Ala Ile Val Ala Val Leu Leu Arg Ser Asp Gln 35 40 45Glu Pro Leu Tyr Pro Val Gln Val Ser Ser Ala Asp Ala Arg Leu Met 50 55 60Val Phe Asp Lys Thr Glu Gly Thr Trp Arg Leu Leu Cys Ser Ser Arg 65 70 7580 Ser Asn Ala Arg Val Ala Gly Leu Ser Cys Glu Glu Met Gly Phe Leu 85 9095 Arg Ala Leu Thr His Ser Glu Leu Asp Val Arg Thr Ala Gly Ala Asn 100105 110 Gly Thr Ser Gly Phe Phe Cys Val Asp Glu Gly Arg Leu Pro His Thr115 120 125 Gln Arg Leu Leu Glu Val Ile Ser Val Cys Asp Cys Pro Arg GlyArg 130 135 140 Phe Leu Ala Ala Ile Cys Gln Asp Cys Gly Arg Arg Lys LeuPro Val 145 150 155 160 Asp Arg Ile Val Gly Gly Arg Asp Thr Ser Leu GlyArg Trp Pro Trp 165 170 175 Gln Val Ser Leu Arg Tyr Asp Gly Ala His LeuCys Gly Gly Ser Leu 180 185 190 Leu Ser Gly Asp Trp Val Leu Thr Ala AlaHis Cys Phe Pro Glu Arg 195 200 205 Asn Arg Val Leu Ser Arg Trp Arg ValPhe Ala Gly Ala Val Ala Gln 210 215 220 Ala Ser Pro His Gly Leu Gln LeuGly Val Gln Ala Val Val Tyr His 225 230 235 240 Gly Gly Tyr Leu Pro PheArg Asp Pro Asn Ser Glu Glu Asn Ser Asn 245 250 255 Asp Ile Ala Leu ValHis Leu Ser Ser Pro Leu Pro Leu Thr Glu Tyr 260 265 270 Ile Gln Pro ValCys Leu Pro Ala Ala Gly Gln Ala Leu Val Asp Gly 275 280 285 Lys Ile CysThr Val Thr Gly Trp Gly Asn Thr Gln Tyr Tyr Gly Gln 290 295 300 Gln AlaGly Val Leu Gln Glu Ala Arg Val Pro Ile Ile Ser Asn Asp 305 310 315 320Val Cys Asn Gly Ala Asp Phe Tyr Gly Asn Gln Ile Lys Pro Lys Met 325 330335 Phe Cys Ala Gly Tyr Pro Glu Gly Gly Ile Asp Ala Cys Gln Gly Asp 340345 350 Ser Gly Gly Pro Phe Val Cys Glu Asp Ser Ile Ser Arg Thr Pro Arg355 360 365 Trp Arg Leu Cys Gly Ile Val Ser Trp Gly Thr Gly Cys Ala LeuAla 370 375 380 Gln Lys Pro Gly Val Tyr Thr Lys Val Ser Asp Phe Arg GluTrp Ile 385 390 395 400 Phe Gln Ala Ile Lys Thr His Ser Glu Ala Ser GlyMet Val Thr Gln 405 410 415 Leu <210> SEQ ID NO 36 <211> LENGTH: 2479<212> TYPE: DNA <213> ORGANISM: Homo sapien <220> FEATURE: <221>NAME/KEY: CDS <222> LOCATION: (57)...(1535) <223> OTHER INFORMATION:Nucleotide sequence encoding human serine protease (TMPRS2) <300>PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank U75329<309> DATABASE ENTRY DATE: 1997-10-10 <400> SEQUENCE: 36 gtcatattgaacattccaga tacctatcat tactcgatgc tgttgataac agcaag atg 59 Met 1 gct ttgaac tca ggg tca cca cca gct att gga cct tac tat gaa aac 107 Ala Leu AsnSer Gly Ser Pro Pro Ala Ile Gly Pro Tyr Tyr Glu Asn 5 10 15 cat gga taccaa ccg gaa aac ccc tat ccc gca cag ccc act gtg gtc 155 His Gly Tyr GlnPro Glu Asn Pro Tyr Pro Ala Gln Pro Thr Val Val 20 25 30 ccc act gtc tacgag gtg cat ccg gct cag tac tac ccg tcc ccc gtg 203 Pro Thr Val Tyr GluVal His Pro Ala Gln Tyr Tyr Pro Ser Pro Val 35 40 45 ccc cag tac gcc ccgagg gtc ctg acg cag gct tcc aac ccc gtc gtc 251 Pro Gln Tyr Ala Pro ArgVal Leu Thr Gln Ala Ser Asn Pro Val Val 50 55 60 65 tgc acg cag ccc aaatcc cca tcc ggg aca gtg tgc acc tca aag act 299 Cys Thr Gln Pro Lys SerPro Ser Gly Thr Val Cys Thr Ser Lys Thr 70 75 80 aag aaa gca ctg tgc atcacc ttg acc ctg ggg acc ttc ctc gtg gga 347 Lys Lys Ala Leu Cys Ile ThrLeu Thr Leu Gly Thr Phe Leu Val Gly 85 90 95 gct gcg ctg gcc gct ggc ctactc tgg aag ttc atg ggc agc aag tgc 395 Ala Ala Leu Ala Ala Gly Leu LeuTrp Lys Phe Met Gly Ser Lys Cys 100 105 110 tcc aac tct ggg ata gag tgcgac tcc tca ggt acc tgc atc aac ccc 443 Ser Asn Ser Gly Ile Glu Cys AspSer Ser Gly Thr Cys Ile Asn Pro 115 120 125 tct aac tgg tgt gat ggc gtgtca cac tgc ccc ggc ggg gag gac gag 491 Ser Asn Trp Cys Asp Gly Val SerHis Cys Pro Gly Gly Glu Asp Glu 130 135 140 145 aat cgg tgt gtt cgc ctctac gga cca aac ttc atc ctt cag atg tac 539 Asn Arg Cys Val Arg Leu TyrGly Pro Asn Phe Ile Leu Gln Met Tyr 150 155 160 tca tct cag agg aag tcctgg cac cct gtg tgc caa gac gac tgg aac 587 Ser Ser Gln Arg Lys Ser TrpHis Pro Val Cys Gln Asp Asp Trp Asn 165 170 175 gag aac tac ggg cgg gcggcc tgc agg gac atg ggc tat aag aat aat 635 Glu Asn Tyr Gly Arg Ala AlaCys Arg Asp Met Gly Tyr Lys Asn Asn 180 185 190 ttt tac tct agc caa ggaata gtg gat gac agc gga tcc acc agc ttt 683 Phe Tyr Ser Ser Gln Gly IleVal Asp Asp Ser Gly Ser Thr Ser Phe 195 200 205 atg aaa ctg aac aca agtgcc ggc aat gtc gat atc tat aaa aaa ctg 731 Met Lys Leu Asn Thr Ser AlaGly Asn Val Asp Ile Tyr Lys Lys Leu 210 215 220 225 tac cac agt gat gcctgt tct tca aaa gca gtg gtt tct tta cgc tgt 779 Tyr His Ser Asp Ala CysSer Ser Lys Ala Val Val Ser Leu Arg Cys 230 235 240 tta gcc tgc ggg gtcaac ttg aac tca agc cgc cag agc agg atc gtg 827 Leu Ala Cys Gly Val AsnLeu Asn Ser Ser Arg Gln Ser Arg Ile Val 245 250 255 ggc ggt gag agc gcgctc ccg ggg gcc tgg ccc tgg cag gtc agc ctg 875 Gly Gly Glu Ser Ala LeuPro Gly Ala Trp Pro Trp Gln Val Ser Leu 260 265 270 cac gtc cag aac gtccac gtg tgc gga ggc tcc atc atc acc ccc gag 923 His Val Gln Asn Val HisVal Cys Gly Gly Ser Ile Ile Thr Pro Glu 275 280 285 tgg atc gtg aca gccgcc cac tgc gtg gaa aaa cct ctt aac aat cca 971 Trp Ile Val Thr Ala AlaHis Cys Val Glu Lys Pro Leu Asn Asn Pro 290 295 300 305 tgg cat tgg acggca ttt gcg ggg att ttg aga caa tct ttc atg ttc 1019 Trp His Trp Thr AlaPhe Ala Gly Ile Leu Arg Gln Ser Phe Met Phe 310 315 320 tat gga gcc ggatac caa gta caa aaa gtg att tct cat cca aat tat 1067 Tyr Gly Ala Gly TyrGln Val Gln Lys Val Ile Ser His Pro Asn Tyr 325 330 335 gac tcc aag accaag aac aat gac att gcg ctg atg aag ctg cag aag 1115 Asp Ser Lys Thr LysAsn Asn Asp Ile Ala Leu Met Lys Leu Gln Lys 340 345 350 cct ctg act ttcaac gac cta gtg aaa cca gtg tgt ctg ccc aac cca 1163 Pro Leu Thr Phe AsnAsp Leu Val Lys Pro Val Cys Leu Pro Asn Pro 355 360 365 ggc atg atg ctgcag cca gaa cag ctc tgc tgg att tcc ggg tgg ggg 1211 Gly Met Met Leu GlnPro Glu Gln Leu Cys Trp Ile Ser Gly Trp Gly 370 375 380 385 gcc acc gaggag aaa ggg aag acc tca gaa gtg ctg aac gct gcc aag 1259 Ala Thr Glu GluLys Gly Lys Thr Ser Glu Val Leu Asn Ala Ala Lys 390 395 400 gtg ctt ctcatt gag aca cag aga tgc aac agc aga tat gtc tat gac 1307 Val Leu Leu IleGlu Thr Gln Arg Cys Asn Ser Arg Tyr Val Tyr Asp 405 410 415 aac ctg atcaca cca gcc atg atc tgt gcc ggc ttc ctg cag ggg aac 1355 Asn Leu Ile ThrPro Ala Met Ile Cys Ala Gly Phe Leu Gln Gly Asn 420 425 430 gtc gat tcttgc cag ggt gac agt gga ggg cct ctg gtc act tcg aac 1403 Val Asp Ser CysGln Gly Asp Ser Gly Gly Pro Leu Val Thr Ser Asn 435 440 445 aac aat atctgg tgg ctg ata ggg gat aca agc tgg ggt tct ggc tgt 1451 Asn Asn Ile TrpTrp Leu Ile Gly Asp Thr Ser Trp Gly Ser Gly Cys 450 455 460 465 gcc aaagct tac aga cca gga gtg tac ggg aat gtg atg gta ttc acg 1499 Ala Lys AlaTyr Arg Pro Gly Val Tyr Gly Asn Val Met Val Phe Thr 470 475 480 gac tggatt tat cga caa atg aag gca aac ggc taa tccacatggt 1545 Asp Trp Ile TyrArg Gln Met Lys Ala Asn Gly * 485 490 cttcgtcctt gacgtcgttt tacaagaaaacaatggggct ggttttgctt ccccgtgcat 1605 gatttactct tagagatgat tcagaggtcacttcattttt attaaacagt gaacttgtct 1665 ggctttggca ctctctgcca tactgtgcaggctgcagtgg ctcccctgcc cagcctgctc 1725 tccctaaccc cttgtccgca aggggtgatggccggctggt tgtgggcact ggcggtcaat 1785 tgtggaagga agagggttgg aggctgcccccattgagatc ttcctgctga gtcctttcca 1845 ggggccaatt ttggatgagc atggagctgtcacttctcag ctgctggatg acttgagatg 1905 aaaaaggaga gacatggaaa gggagacagccaggtggcac ctgcagcggc tgccctctgg 1965 ggccacttgg tagtgtcccc agcctacttcacaaggggat tttgctgatg ggttcttaga 2025 gccttagcag ccctggatgg tggccagaaataaagggacc agcccttcat gggtggtgac 2085 gtggtagtca cttgtaaggg gaacagaaacatttttgttc ttatggggtg agaatataga 2145 cagtgccctt ggtgcgaggg aagcaattgaaaaggaactt gccctgagca ctcctggtgc 2205 aggtctccac ctgcacattg ggtggggctcctgggaggga gactcagcct tcctcctcat 2265 cctccctgac cctgctccta gcaccctggagagtgaatgc cccttggtcc ctggcagggc 2325 gccaagtttg gcaccatgtc ggcctcttcaggcctgatag tcattggaaa ttgaggtcca 2385 tgggggaaat caaggatgct cagtttaaggtacactgttt ccatgttatg tttctacaca 2445 ttgatggtgg tgaccctgag ttcaaagccatctt 2479 <210> SEQ ID NO 37 <211> LENGTH: 492 <212> TYPE: PRT <213>ORGANISM: Homo sapien <400> SEQUENCE: 37 Met Ala Leu Asn Ser Gly Ser ProPro Ala Ile Gly Pro Tyr Tyr Glu 1 5 10 15 Asn His Gly Tyr Gln Pro GluAsn Pro Tyr Pro Ala Gln Pro Thr Val 20 25 30 Val Pro Thr Val Tyr Glu ValHis Pro Ala Gln Tyr Tyr Pro Ser Pro 35 40 45 Val Pro Gln Tyr Ala Pro ArgVal Leu Thr Gln Ala Ser Asn Pro Val 50 55 60 Val Cys Thr Gln Pro Lys SerPro Ser Gly Thr Val Cys Thr Ser Lys 65 70 75 80 Thr Lys Lys Ala Leu CysIle Thr Leu Thr Leu Gly Thr Phe Leu Val 85 90 95 Gly Ala Ala Leu Ala AlaGly Leu Leu Trp Lys Phe Met Gly Ser Lys 100 105 110 Cys Ser Asn Ser GlyIle Glu Cys Asp Ser Ser Gly Thr Cys Ile Asn 115 120 125 Pro Ser Asn TrpCys Asp Gly Val Ser His Cys Pro Gly Gly Glu Asp 130 135 140 Glu Asn ArgCys Val Arg Leu Tyr Gly Pro Asn Phe Ile Leu Gln Met 145 150 155 160 TyrSer Ser Gln Arg Lys Ser Trp His Pro Val Cys Gln Asp Asp Trp 165 170 175Asn Glu Asn Tyr Gly Arg Ala Ala Cys Arg Asp Met Gly Tyr Lys Asn 180 185190 Asn Phe Tyr Ser Ser Gln Gly Ile Val Asp Asp Ser Gly Ser Thr Ser 195200 205 Phe Met Lys Leu Asn Thr Ser Ala Gly Asn Val Asp Ile Tyr Lys Lys210 215 220 Leu Tyr His Ser Asp Ala Cys Ser Ser Lys Ala Val Val Ser LeuArg 225 230 235 240 Cys Leu Ala Cys Gly Val Asn Leu Asn Ser Ser Arg GlnSer Arg Ile 245 250 255 Val Gly Gly Glu Ser Ala Leu Pro Gly Ala Trp ProTrp Gln Val Ser 260 265 270 Leu His Val Gln Asn Val His Val Cys Gly GlySer Ile Ile Thr Pro 275 280 285 Glu Trp Ile Val Thr Ala Ala His Cys ValGlu Lys Pro Leu Asn Asn 290 295 300 Pro Trp His Trp Thr Ala Phe Ala GlyIle Leu Arg Gln Ser Phe Met 305 310 315 320 Phe Tyr Gly Ala Gly Tyr GlnVal Gln Lys Val Ile Ser His Pro Asn 325 330 335 Tyr Asp Ser Lys Thr LysAsn Asn Asp Ile Ala Leu Met Lys Leu Gln 340 345 350 Lys Pro Leu Thr PheAsn Asp Leu Val Lys Pro Val Cys Leu Pro Asn 355 360 365 Pro Gly Met MetLeu Gln Pro Glu Gln Leu Cys Trp Ile Ser Gly Trp 370 375 380 Gly Ala ThrGlu Glu Lys Gly Lys Thr Ser Glu Val Leu Asn Ala Ala 385 390 395 400 LysVal Leu Leu Ile Glu Thr Gln Arg Cys Asn Ser Arg Tyr Val Tyr 405 410 415Asp Asn Leu Ile Thr Pro Ala Met Ile Cys Ala Gly Phe Leu Gln Gly 420 425430 Asn Val Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Thr Ser 435440 445 Asn Asn Asn Ile Trp Trp Leu Ile Gly Asp Thr Ser Trp Gly Ser Gly450 455 460 Cys Ala Lys Ala Tyr Arg Pro Gly Val Tyr Gly Asn Val Met ValPhe 465 470 475 480 Thr Asp Trp Ile Tyr Arg Gln Met Lys Ala Asn Gly 485490 <210> SEQ ID NO 38 <211> LENGTH: 2079 <212> TYPE: DNA <213>ORGANISM: Homo sapien <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(251)...(1522) <223> OTHER INFORMATION: Nucleotide sequence encodingtransmembrane protease, serine 4 (TMPRSS4) <300> PUBLICATIONINFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank NM016425 <309>DATABASE ENTRY DATE: 2000-11-06 <400> SEQUENCE: 38 gagaggcagc agcttgttcagcggacaagg atgctgggcg tgagggacca aggcctgccc 60 tgcactcggg cctcctccagccagtgctga ccagggactt ctgacctgct ggccagccag 120 gacctgtgtg gggaggccctcctgctgcct tggggtgaca atctcagctc caggctacag 180 ggagaccggg aggatcacagagccagcatg gtacaggatc ctgacagtga tcaacctctg 240 aacagcctcg atg tca aacccc tgc gca aac ccc gta tcc cca tgg aga 289 Met Ser Asn Pro Cys Ala AsnPro Val Ser Pro Trp Arg 1 5 10 cct tca gaa agt gtg ggg atc ccc atc atcata gca cta ctg agc ctg 337 Pro Ser Glu Ser Val Gly Ile Pro Ile Ile IleAla Leu Leu Ser Leu 15 20 25 gcg agt atc atc att gtg gtt gtc ctc atc aaggtg att ctg gat aaa 385 Ala Ser Ile Ile Ile Val Val Val Leu Ile Lys ValIle Leu Asp Lys 30 35 40 45 tac tac ttc ctc tgc ggg cag cct ctc cac ttcatc ccg agg aag cag 433 Tyr Tyr Phe Leu Cys Gly Gln Pro Leu His Phe IlePro Arg Lys Gln 50 55 60 ctg tgt gac gga gag ctg gac tgt ccc ttg ggg gaggac gag gag cac 481 Leu Cys Asp Gly Glu Leu Asp Cys Pro Leu Gly Glu AspGlu Glu His 65 70 75 tgt gtc aag agc ttc ccc gaa ggg cct gca gtg gca gtccgc ctc tcc 529 Cys Val Lys Ser Phe Pro Glu Gly Pro Ala Val Ala Val ArgLeu Ser 80 85 90 aag gac cga tcc aca ctg cag gtg ctg gac tcg gcc aca gggaac tgg 577 Lys Asp Arg Ser Thr Leu Gln Val Leu Asp Ser Ala Thr Gly AsnTrp 95 100 105 ttc tct gcc tgt ttc gac aac ttc aca gaa gct ctc gct gagaca gcc 625 Phe Ser Ala Cys Phe Asp Asn Phe Thr Glu Ala Leu Ala Glu ThrAla 110 115 120 125 tgt agg cag atg ggc tac agc agc aaa ccc act ttc agagct gtg gag 673 Cys Arg Gln Met Gly Tyr Ser Ser Lys Pro Thr Phe Arg AlaVal Glu 130 135 140 att ggc cca gac cag gat ctg gat gtt gtt gaa atc acagaa aac agc 721 Ile Gly Pro Asp Gln Asp Leu Asp Val Val Glu Ile Thr GluAsn Ser 145 150 155 cag gag ctt cgc atg cgg aac tca agt ggg ccc tgt ctctca ggc tcc 769 Gln Glu Leu Arg Met Arg Asn Ser Ser Gly Pro Cys Leu SerGly Ser 160 165 170 ctg gtc tcc ctg cac tgt ctt gcc tgt ggg aag agc ctgaag acc ccc 817 Leu Val Ser Leu His Cys Leu Ala Cys Gly Lys Ser Leu LysThr Pro 175 180 185 cgt gtg gtg ggt ggg gag gag gcc tct gtg gat tct tggcct tgg cag 865 Arg Val Val Gly Gly Glu Glu Ala Ser Val Asp Ser Trp ProTrp Gln 190 195 200 205 gtc agc atc cag tac gac aaa cag cac gtc tgt ggaggg agc atc ctg 913 Val Ser Ile Gln Tyr Asp Lys Gln His Val Cys Gly GlySer Ile Leu 210 215 220 gac ccc cac tgg gtc ctc acg gca gcc cac tgc ttcagg aaa cat acc 961 Asp Pro His Trp Val Leu Thr Ala Ala His Cys Phe ArgLys His Thr 225 230 235 gat gtg ttc aac tgg aag gtg cgg gca ggc tca gacaaa ctg ggc agc 1009 Asp Val Phe Asn Trp Lys Val Arg Ala Gly Ser Asp LysLeu Gly Ser 240 245 250 ttc cca tcc ctg gct gtg gcc aag atc atc atc attgaa ttc aac ccc 1057 Phe Pro Ser Leu Ala Val Ala Lys Ile Ile Ile Ile GluPhe Asn Pro 255 260 265 atg tac ccc aaa gac aat gac atc gcc ctc atg aagctg cag ttc cca 1105 Met Tyr Pro Lys Asp Asn Asp Ile Ala Leu Met Lys LeuGln Phe Pro 270 275 280 285 ctc act ttc tca ggc aca gtc agg ccc atc tgtctg ccc ttc ttt gat 1153 Leu Thr Phe Ser Gly Thr Val Arg Pro Ile Cys LeuPro Phe Phe Asp 290 295 300 gag gag ctc act cca gcc acc cca ctc tgg atcatt gga tgg ggc ttt 1201 Glu Glu Leu Thr Pro Ala Thr Pro Leu Trp Ile IleGly Trp Gly Phe 305 310 315 acg aag cag aat gga ggg aag atg tct gac atactg ctg cag gcg tca 1249 Thr Lys Gln Asn Gly Gly Lys Met Ser Asp Ile LeuLeu Gln Ala Ser 320 325 330 gtc cag gtc att gac agc aca cgg tgc aat gcagac gat gcg tac cag 1297 Val Gln Val Ile Asp Ser Thr Arg Cys Asn Ala AspAsp Ala Tyr Gln 335 340 345 ggg gaa gtc acc gag aag atg atg tgt gca ggcatc ccg gaa ggg ggt 1345 Gly Glu Val Thr Glu Lys Met Met Cys Ala Gly IlePro Glu Gly Gly 350 355 360 365 gtg gac acc tgc cag ggt gac agt ggt gggccc ctg atg tac caa tct 1393 Val Asp Thr Cys Gln Gly Asp Ser Gly Gly ProLeu Met Tyr Gln Ser 370 375 380 gac cag tgg cat gtg gtg ggc atc gtt agctgg ggc tat ggc tgc ggg 1441 Asp Gln Trp His Val Val Gly Ile Val Ser TrpGly Tyr Gly Cys Gly 385 390 395 ggc ccg agc acc cca gga gta tac acc aaggtc tca gcc tat ctc aac 1489 Gly Pro Ser Thr Pro Gly Val Tyr Thr Lys ValSer Ala Tyr Leu Asn 400 405 410 tgg atc tac aat gtc tgg aag gct gag ctgtaa tgctgctgcc cctttgcagt 1542 Trp Ile Tyr Asn Val Trp Lys Ala Glu Leu *415 420 gctgggagcc gcttccttcc tgccctgccc acctggggat cccccaaagtcagacacaga 1602 gcaagagtcc ccttgggtac acccctctgc ccacagcctc agcatttcttggagcagcaa 1662 agggcctcaa ttcctgtaag agaccctcgc agcccagagg cgcccagaggaagtcagcag 1722 ccctagctcg gccacacttg gtgctcccag catcccaggg agagacacagcccactgaac 1782 aaggtctcag gggtattgct aagccaagaa ggaactttcc cacactactgaatggaagca 1842 ggctgtcttg taaaagccca gatcactgtg ggctggagag gagaaggaaagggtctgcgc 1902 cagccctgtc cgtcttcacc catccccaag cctactagag caagaaaccagttgtaatat 1962 aaaatgcact gccctactgt tggtatgact accgttacct actgttgtcattgttattac 2022 agctatggcc actattatta aagagctgtg taacatcaaa aaaaaaaaaaaaaaaaa 2079 <210> SEQ ID NO 39 <211> LENGTH: 423 <212> TYPE: PRT <213>ORGANISM: Homo sapien <400> SEQUENCE: 39 Met Ser Asn Pro Cys Ala Asn ProVal Ser Pro Trp Arg Pro Ser Glu 1 5 10 15 Ser Val Gly Ile Pro Ile IleIle Ala Leu Leu Ser Leu Ala Ser Ile 20 25 30 Ile Ile Val Val Val Leu IleLys Val Ile Leu Asp Lys Tyr Tyr Phe 35 40 45 Leu Cys Gly Gln Pro Leu HisPhe Ile Pro Arg Lys Gln Leu Cys Asp 50 55 60 Gly Glu Leu Asp Cys Pro LeuGly Glu Asp Glu Glu His Cys Val Lys 65 70 75 80 Ser Phe Pro Glu Gly ProAla Val Ala Val Arg Leu Ser Lys Asp Arg 85 90 95 Ser Thr Leu Gln Val LeuAsp Ser Ala Thr Gly Asn Trp Phe Ser Ala 100 105 110 Cys Phe Asp Asn PheThr Glu Ala Leu Ala Glu Thr Ala Cys Arg Gln 115 120 125 Met Gly Tyr SerSer Lys Pro Thr Phe Arg Ala Val Glu Ile Gly Pro 130 135 140 Asp Gln AspLeu Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu 145 150 155 160 ArgMet Arg Asn Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser 165 170 175Leu His Cys Leu Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val 180 185190 Gly Gly Glu Glu Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile 195200 205 Gln Tyr Asp Lys Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His210 215 220 Trp Val Leu Thr Ala Ala His Cys Phe Arg Lys His Thr Asp ValPhe 225 230 235 240 Asn Trp Lys Val Arg Ala Gly Ser Asp Lys Leu Gly SerPhe Pro Ser 245 250 255 Leu Ala Val Ala Lys Ile Ile Ile Ile Glu Phe AsnPro Met Tyr Pro 260 265 270 Lys Asp Asn Asp Ile Ala Leu Met Lys Leu GlnPhe Pro Leu Thr Phe 275 280 285 Ser Gly Thr Val Arg Pro Ile Cys Leu ProPhe Phe Asp Glu Glu Leu 290 295 300 Thr Pro Ala Thr Pro Leu Trp Ile IleGly Trp Gly Phe Thr Lys Gln 305 310 315 320 Asn Gly Gly Lys Met Ser AspIle Leu Leu Gln Ala Ser Val Gln Val 325 330 335 Ile Asp Ser Thr Arg CysAsn Ala Asp Asp Ala Tyr Gln Gly Glu Val 340 345 350 Thr Glu Lys Met MetCys Ala Gly Ile Pro Glu Gly Gly Val Asp Thr 355 360 365 Cys Gln Gly AspSer Gly Gly Pro Leu Met Tyr Gln Ser Asp Gln Trp 370 375 380 His Val ValGly Ile Val Ser Trp Gly Tyr Gly Cys Gly Gly Pro Ser 385 390 395 400 ThrPro Gly Val Tyr Thr Lys Val Ser Ala Tyr Leu Asn Trp Ile Tyr 405 410 415Asn Val Trp Lys Ala Glu Leu 420 <210> SEQ ID NO 40 <211> LENGTH: 1471<212> TYPE: DNA <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: DESC1 gene <220> FEATURE: <221> NAME/KEY:misc_feature <222> LOCATION: (626)...(1324) <223> OTHER INFORMATION:protease domain <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(56)...(1324) <400> SEQUENCE: 40 tgacttggat gtagacctcg accttcacaggactcttcat tgctggttgg caatg atg 58 Met 1 tat cgg cca gat gtg gtg agg gctagg aaa aga gtt tgt tgg gaa ccc 106 Tyr Arg Pro Asp Val Val Arg Ala ArgLys Arg Val Cys Trp Glu Pro 5 10 15 tgg gtt atc ggc ctc gtc ats ttc atatcc ctg att gtc ctg gca gtg 154 Trp Val Ile Gly Leu Val Xaa Phe Ile SerLeu Ile Val Leu Ala Val 20 25 30 tgc att gga stc act gtt cat tat gtg agatat aat caa aag aag acc 202 Cys Ile Gly Xaa Thr Val His Tyr Val Arg TyrAsn Gln Lys Lys Thr 35 40 45 tac aat tac tat agc aca ttg tca ttt aca actgac aaa cta tat gct 250 Tyr Asn Tyr Tyr Ser Thr Leu Ser Phe Thr Thr AspLys Leu Tyr Ala 50 55 60 65 gag ttt ggc aga gag gct tct aac aat ttt acagaa atg agc cag aga 298 Glu Phe Gly Arg Glu Ala Ser Asn Asn Phe Thr GluMet Ser Gln Arg 70 75 80 ctt gaa tca atg gtg aaa aat gca ttt tat aaa tctcca tta agg gaa 346 Leu Glu Ser Met Val Lys Asn Ala Phe Tyr Lys Ser ProLeu Arg Glu 85 90 95 gaa ttt gtc aag tct cag gtt atc aag ttc agt caa cagaag cat gga 394 Glu Phe Val Lys Ser Gln Val Ile Lys Phe Ser Gln Gln LysHis Gly 100 105 110 gtg ttg gct cat atg ctg ttg att tgt aga ttt cac tctact gag gat 442 Val Leu Ala His Met Leu Leu Ile Cys Arg Phe His Ser ThrGlu Asp 115 120 125 cct gaa act gta gat aaa att gtt caa ctt gtt tta catgaa aag ctg 490 Pro Glu Thr Val Asp Lys Ile Val Gln Leu Val Leu His GluLys Leu 130 135 140 145 caa gat gct gta gga ccc cct aaa gta gat cct cactca gtt aaa att 538 Gln Asp Ala Val Gly Pro Pro Lys Val Asp Pro His SerVal Lys Ile 150 155 160 aaa aaa atc aac aag aca gaa aca gac agc tat ctaaac cat tgc tgc 586 Lys Lys Ile Asn Lys Thr Glu Thr Asp Ser Tyr Leu AsnHis Cys Cys 165 170 175 gga aca cga aga agt aaa act cta ggt cag agt ctcagg atc gtt ggt 634 Gly Thr Arg Arg Ser Lys Thr Leu Gly Gln Ser Leu ArgIle Val Gly 180 185 190 ggg aca gaa gta gaa gag ggt gaa tgg ccc tgg caggct agc ctg cag 682 Gly Thr Glu Val Glu Glu Gly Glu Trp Pro Trp Gln AlaSer Leu Gln 195 200 205 tgg gat ggg agt cat cgc tgt gga gca acc tta attaat gcc aca tgg 730 Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu Ile AsnAla Thr Trp 210 215 220 225 ctt gtg agt gct gct cac tgt ttt aca aca tataag aac cct gcc aga 778 Leu Val Ser Ala Ala His Cys Phe Thr Thr Tyr LysAsn Pro Ala Arg 230 235 240 tgg act gct tcc ttt gga gta aca ata aaa ccttcg aaa atg aaa cgg 826 Trp Thr Ala Ser Phe Gly Val Thr Ile Lys Pro SerLys Met Lys Arg 245 250 255 ggt ctc cgg aga ata att gtc cat gaa aaa tacaaa cac cca tca cat 874 Gly Leu Arg Arg Ile Ile Val His Glu Lys Tyr LysHis Pro Ser His 260 265 270 gac tat gat att tct ctt gca gag ctt tct agccct gtt ccc tac aca 922 Asp Tyr Asp Ile Ser Leu Ala Glu Leu Ser Ser ProVal Pro Tyr Thr 275 280 285 aat gca gta cat aga gtt tgt ctc cct gat gcatcc tat gag ttt caa 970 Asn Ala Val His Arg Val Cys Leu Pro Asp Ala SerTyr Glu Phe Gln 290 295 300 305 cca ggt gat gtg atg ttt gtg aca gga tttgga gca ctg aaa aat gat 1018 Pro Gly Asp Val Met Phe Val Thr Gly Phe GlyAla Leu Lys Asn Asp 310 315 320 ggt tac agt caa aat cat ctt cga caa gcacag gtg act ctc ata gac 1066 Gly Tyr Ser Gln Asn His Leu Arg Gln Ala GlnVal Thr Leu Ile Asp 325 330 335 gct aca act tgc aat gaa cct caa gct tacaat gac gcc ata act cct 1114 Ala Thr Thr Cys Asn Glu Pro Gln Ala Tyr AsnAsp Ala Ile Thr Pro 340 345 350 aga atg tta tgt gct ggc tcc tta gaa ggaaaa aca gat gca tgc cag 1162 Arg Met Leu Cys Ala Gly Ser Leu Glu Gly LysThr Asp Ala Cys Gln 355 360 365 ggt gac tct gga gga cca ctg gtt agt tcagat gct aga gat atc tgg 1210 Gly Asp Ser Gly Gly Pro Leu Val Ser Ser AspAla Arg Asp Ile Trp 370 375 380 385 tac ctt gct gga ata gtg agc tsg ggagat gaa tgt gcg aaa ccc aac 1258 Tyr Leu Ala Gly Ile Val Ser Xaa Gly AspGlu Cys Ala Lys Pro Asn 390 395 400 aag cct ggt gtt tat act aga gtt acggcc ttg cgg gac tgg att act 1306 Lys Pro Gly Val Tyr Thr Arg Val Thr AlaLeu Arg Asp Trp Ile Thr 405 410 415 tca aaa act ggt atc taa gagagaaaagcctcatggaa cagataacat 1354 Ser Lys Thr Gly Ile * 420 ttttttttgttttttgggtg tggaggccat ttttagagat acagaattgg agaagacttg 1414 caaaacagctagatttgact gatctcaata aactgtttgc ttgatgcaaa aaaaaaa 1471 <210> SEQ ID NO41 <211> LENGTH: 422 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <220>FEATURE: <221> NAME/KEY: VARIANT <222> LOCATION: 24 <223> OTHERINFORMATION: Xaa is Ile or Met <220> FEATURE: <221> NAME/KEY: VARIANT<222> LOCATION: 37 <223> OTHER INFORMATION: Xaa is Leu or Val <220>FEATURE: <221> NAME/KEY: VARIANT <222> LOCATION: 393 <223> OTHERINFORMATION: Xaa is Ser or Trp <400> SEQUENCE: 41 Met Tyr Arg Pro AspVal Val Arg Ala Arg Lys Arg Val Cys Trp Glu 1 5 10 15 Pro Trp Val IleGly Leu Val Xaa Phe Ile Ser Leu Ile Val Leu Ala 20 25 30 Val Cys Ile GlyXaa Thr Val His Tyr Val Arg Tyr Asn Gln Lys Lys 35 40 45 Thr Tyr Asn TyrTyr Ser Thr Leu Ser Phe Thr Thr Asp Lys Leu Tyr 50 55 60 Ala Glu Phe GlyArg Glu Ala Ser Asn Asn Phe Thr Glu Met Ser Gln 65 70 75 80 Arg Leu GluSer Met Val Lys Asn Ala Phe Tyr Lys Ser Pro Leu Arg 85 90 95 Glu Glu PheVal Lys Ser Gln Val Ile Lys Phe Ser Gln Gln Lys His 100 105 110 Gly ValLeu Ala His Met Leu Leu Ile Cys Arg Phe His Ser Thr Glu 115 120 125 AspPro Glu Thr Val Asp Lys Ile Val Gln Leu Val Leu His Glu Lys 130 135 140Leu Gln Asp Ala Val Gly Pro Pro Lys Val Asp Pro His Ser Val Lys 145 150155 160 Ile Lys Lys Ile Asn Lys Thr Glu Thr Asp Ser Tyr Leu Asn His Cys165 170 175 Cys Gly Thr Arg Arg Ser Lys Thr Leu Gly Gln Ser Leu Arg IleVal 180 185 190 Gly Gly Thr Glu Val Glu Glu Gly Glu Trp Pro Trp Gln AlaSer Leu 195 200 205 Gln Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu IleAsn Ala Thr 210 215 220 Trp Leu Val Ser Ala Ala His Cys Phe Thr Thr TyrLys Asn Pro Ala 225 230 235 240 Arg Trp Thr Ala Ser Phe Gly Val Thr IleLys Pro Ser Lys Met Lys 245 250 255 Arg Gly Leu Arg Arg Ile Ile Val HisGlu Lys Tyr Lys His Pro Ser 260 265 270 His Asp Tyr Asp Ile Ser Leu AlaGlu Leu Ser Ser Pro Val Pro Tyr 275 280 285 Thr Asn Ala Val His Arg ValCys Leu Pro Asp Ala Ser Tyr Glu Phe 290 295 300 Gln Pro Gly Asp Val MetPhe Val Thr Gly Phe Gly Ala Leu Lys Asn 305 310 315 320 Asp Gly Tyr SerGln Asn His Leu Arg Gln Ala Gln Val Thr Leu Ile 325 330 335 Asp Ala ThrThr Cys Asn Glu Pro Gln Ala Tyr Asn Asp Ala Ile Thr 340 345 350 Pro ArgMet Leu Cys Ala Gly Ser Leu Glu Gly Lys Thr Asp Ala Cys 355 360 365 GlnGly Asp Ser Gly Gly Pro Leu Val Ser Ser Asp Ala Arg Asp Ile 370 375 380Trp Tyr Leu Ala Gly Ile Val Ser Xaa Gly Asp Glu Cys Ala Lys Pro 385 390395 400 Asn Lys Pro Gly Val Tyr Thr Arg Val Thr Ala Leu Arg Asp Trp Ile405 410 415 Thr Ser Lys Thr Gly Ile 420 <210> SEQ ID NO 42 <211> LENGTH:1257 <212> TYPE: DNA <213> ORGANISM: Homo sapien <220> FEATURE: <221>NAME/KEY: CDS <222> LOCATION: (1)...(1257) <223> OTHER INFORMATION:Nucleotide sequence encoding MTSP9 <400> SEQUENCE: 42 atg atg tat cggaca gta gga ttt ggc acc cga agc aga aat ctg aag 48 Met Met Tyr Arg ThrVal Gly Phe Gly Thr Arg Ser Arg Asn Leu Lys 1 5 10 15 cca tgg atg attgcc gtt ctc att gtg ttg tcc ctg aca gtg gtg gca 96 Pro Trp Met Ile AlaVal Leu Ile Val Leu Ser Leu Thr Val Val Ala 20 25 30 gtg acc ata ggt ctcctg gtt cac ttc cta gta ttt gac caa aaa aag 144 Val Thr Ile Gly Leu LeuVal His Phe Leu Val Phe Asp Gln Lys Lys 35 40 45 gag tac tat cat ggc tccttt aaa att tta gat cca caa atc aat aac 192 Glu Tyr Tyr His Gly Ser PheLys Ile Leu Asp Pro Gln Ile Asn Asn 50 55 60 aat ttc gga caa agc aac acatat caa ctt aag gac tta cga gag acg 240 Asn Phe Gly Gln Ser Asn Thr TyrGln Leu Lys Asp Leu Arg Glu Thr 65 70 75 80 acc gaa aat ttg gtg gat gagata ttt ata gat tca gcc tgg aag aaa 288 Thr Glu Asn Leu Val Asp Glu IlePhe Ile Asp Ser Ala Trp Lys Lys 85 90 95 aat tat atc aag aac caa gta gtcaga ctg act cca gag gaa gat ggt 336 Asn Tyr Ile Lys Asn Gln Val Val ArgLeu Thr Pro Glu Glu Asp Gly 100 105 110 gtg aaa gta gat gtc att atg gtgttc cag ttc ccc tct act gaa caa 384 Val Lys Val Asp Val Ile Met Val PheGln Phe Pro Ser Thr Glu Gln 115 120 125 agg gca gta aga gag aag aaa atccaa agc atc tta aat cag aag ata 432 Arg Ala Val Arg Glu Lys Lys Ile GlnSer Ile Leu Asn Gln Lys Ile 130 135 140 agg aat tta aga gcc ttg cca ataaat gcc tca tca gtt caa gtt aat 480 Arg Asn Leu Arg Ala Leu Pro Ile AsnAla Ser Ser Val Gln Val Asn 145 150 155 160 gca atg agc tca tca aca ggggag tta act gtc caa gca agt tgt ggt 528 Ala Met Ser Ser Ser Thr Gly GluLeu Thr Val Gln Ala Ser Cys Gly 165 170 175 aaa cga gtt gtt cca tta aacgtc aac aga ata gca tct gga gtc att 576 Lys Arg Val Val Pro Leu Asn ValAsn Arg Ile Ala Ser Gly Val Ile 180 185 190 gca ccc aag gcg gcc tgg ccttgg caa gct tcc ctt cag tat gat aac 624 Ala Pro Lys Ala Ala Trp Pro TrpGln Ala Ser Leu Gln Tyr Asp Asn 195 200 205 atc cat cag tgt ggg gcc accttg att agt aac aca tgg ctt gtc act 672 Ile His Gln Cys Gly Ala Thr LeuIle Ser Asn Thr Trp Leu Val Thr 210 215 220 gca gca cac tgc ttc cag aagtat aaa aat cca cat caa tgg act gtt 720 Ala Ala His Cys Phe Gln Lys TyrLys Asn Pro His Gln Trp Thr Val 225 230 235 240 agt ttt gga aca aaa atcaac cct ccc tta atg aaa aga aat gtc aga 768 Ser Phe Gly Thr Lys Ile AsnPro Pro Leu Met Lys Arg Asn Val Arg 245 250 255 aga ttt att atc cat gagaag tac cgc tct gca gca aga gag tac gac 816 Arg Phe Ile Ile His Glu LysTyr Arg Ser Ala Ala Arg Glu Tyr Asp 260 265 270 att gct gtt gtg cag gtctct tcc aga gtc acc ttt tcg gat gac ata 864 Ile Ala Val Val Gln Val SerSer Arg Val Thr Phe Ser Asp Asp Ile 275 280 285 cgc cgg att tgt ttg ccagaa gcc tct gca tcc ttc caa cca aat ttg 912 Arg Arg Ile Cys Leu Pro GluAla Ser Ala Ser Phe Gln Pro Asn Leu 290 295 300 act gtc cac atc aca ggattt gga gca ctt tac tat ggt ggg gaa tcc 960 Thr Val His Ile Thr Gly PheGly Ala Leu Tyr Tyr Gly Gly Glu Ser 305 310 315 320 caa aat gat ctc cgagaa gcc aga gtg aaa atc ata agt gac gat gtc 1008 Gln Asn Asp Leu Arg GluAla Arg Val Lys Ile Ile Ser Asp Asp Val 325 330 335 tgc aag caa cca caggtg tat ggc aat gat ata aaa cct gga atg ttc 1056 Cys Lys Gln Pro Gln ValTyr Gly Asn Asp Ile Lys Pro Gly Met Phe 340 345 350 tgt gcc gga tat atggaa gga att tat gat gcc tgc agg ggt gat tct 1104 Cys Ala Gly Tyr Met GluGly Ile Tyr Asp Ala Cys Arg Gly Asp Ser 355 360 365 ggg gga cct tta gtcaca agg gat ctg aaa gat acg tgg tat ctc att 1152 Gly Gly Pro Leu Val ThrArg Asp Leu Lys Asp Thr Trp Tyr Leu Ile 370 375 380 gga att gta agc tgggga gat aac tgt ggt caa aag gac aag cct gga 1200 Gly Ile Val Ser Trp GlyAsp Asn Cys Gly Gln Lys Asp Lys Pro Gly 385 390 395 400 gtc tac aca caagtg act tat tac cga aac tgg att gct tca aaa aca 1248 Val Tyr Thr Gln ValThr Tyr Tyr Arg Asn Trp Ile Ala Ser Lys Thr 405 410 415 ggc atc taa 1257Gly Ile * <210> SEQ ID NO 43 <211> LENGTH: 418 <212> TYPE: PRT <213>ORGANISM: Homo sapien <400> SEQUENCE: 43 Met Met Tyr Arg Thr Val Gly PheGly Thr Arg Ser Arg Asn Leu Lys 1 5 10 15 Pro Trp Met Ile Ala Val LeuIle Val Leu Ser Leu Thr Val Val Ala 20 25 30 Val Thr Ile Gly Leu Leu ValHis Phe Leu Val Phe Asp Gln Lys Lys 35 40 45 Glu Tyr Tyr His Gly Ser PheLys Ile Leu Asp Pro Gln Ile Asn Asn 50 55 60 Asn Phe Gly Gln Ser Asn ThrTyr Gln Leu Lys Asp Leu Arg Glu Thr 65 70 75 80 Thr Glu Asn Leu Val AspGlu Ile Phe Ile Asp Ser Ala Trp Lys Lys 85 90 95 Asn Tyr Ile Lys Asn GlnVal Val Arg Leu Thr Pro Glu Glu Asp Gly 100 105 110 Val Lys Val Asp ValIle Met Val Phe Gln Phe Pro Ser Thr Glu Gln 115 120 125 Arg Ala Val ArgGlu Lys Lys Ile Gln Ser Ile Leu Asn Gln Lys Ile 130 135 140 Arg Asn LeuArg Ala Leu Pro Ile Asn Ala Ser Ser Val Gln Val Asn 145 150 155 160 AlaMet Ser Ser Ser Thr Gly Glu Leu Thr Val Gln Ala Ser Cys Gly 165 170 175Lys Arg Val Val Pro Leu Asn Val Asn Arg Ile Ala Ser Gly Val Ile 180 185190 Ala Pro Lys Ala Ala Trp Pro Trp Gln Ala Ser Leu Gln Tyr Asp Asn 195200 205 Ile His Gln Cys Gly Ala Thr Leu Ile Ser Asn Thr Trp Leu Val Thr210 215 220 Ala Ala His Cys Phe Gln Lys Tyr Lys Asn Pro His Gln Trp ThrVal 225 230 235 240 Ser Phe Gly Thr Lys Ile Asn Pro Pro Leu Met Lys ArgAsn Val Arg 245 250 255 Arg Phe Ile Ile His Glu Lys Tyr Arg Ser Ala AlaArg Glu Tyr Asp 260 265 270 Ile Ala Val Val Gln Val Ser Ser Arg Val ThrPhe Ser Asp Asp Ile 275 280 285 Arg Arg Ile Cys Leu Pro Glu Ala Ser AlaSer Phe Gln Pro Asn Leu 290 295 300 Thr Val His Ile Thr Gly Phe Gly AlaLeu Tyr Tyr Gly Gly Glu Ser 305 310 315 320 Gln Asn Asp Leu Arg Glu AlaArg Val Lys Ile Ile Ser Asp Asp Val 325 330 335 Cys Lys Gln Pro Gln ValTyr Gly Asn Asp Ile Lys Pro Gly Met Phe 340 345 350 Cys Ala Gly Tyr MetGlu Gly Ile Tyr Asp Ala Cys Arg Gly Asp Ser 355 360 365 Gly Gly Pro LeuVal Thr Arg Asp Leu Lys Asp Thr Trp Tyr Leu Ile 370 375 380 Gly Ile ValSer Trp Gly Asp Asn Cys Gly Gln Lys Asp Lys Pro Gly 385 390 395 400 ValTyr Thr Gln Val Thr Tyr Tyr Arg Asn Trp Ile Ala Ser Lys Thr 405 410 415Gly Ile <210> SEQ ID NO 44 <211> LENGTH: 2130 <212> TYPE: DNA <213>ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(1)...(2104) <223> OTHER INFORMATION: Nucleotide sequence encodingMTSP10, including MTSP10 protease domain <400> SEQUENCE: 44 ata aac ctggtt tat aca aca tct gcc ttc tcc aaa ttt tat gag cag 48 Ile Asn Leu ValTyr Thr Thr Ser Ala Phe Ser Lys Phe Tyr Glu Gln 1 5 10 15 tct gtt gttgca gat gtc agc agc aac aac aaa ggc ggc ctc ctt gtc 96 Ser Val Val AlaAsp Val Ser Ser Asn Asn Lys Gly Gly Leu Leu Val 20 25 30 cac ttt tgg attgtt ttt gtc atg cca cgt gcc aaa ggc cac atc ttc 144 His Phe Trp Ile ValPhe Val Met Pro Arg Ala Lys Gly His Ile Phe 35 40 45 tgt gaa gac tgt gttgcc gcc atc ttg aag gac tcc atc cag aca agc 192 Cys Glu Asp Cys Val AlaAla Ile Leu Lys Asp Ser Ile Gln Thr Ser 50 55 60 atc ata aac cgg acc tctgtg ggg agc ttg cag gga ctg gct gtg gac 240 Ile Ile Asn Arg Thr Ser ValGly Ser Leu Gln Gly Leu Ala Val Asp 65 70 75 80 atg gac tct gtg gta ctaaat gct ggg ctt cgg tca gat tac tcg tca 288 Met Asp Ser Val Val Leu AsnAla Gly Leu Arg Ser Asp Tyr Ser Ser 85 90 95 acc ata gga tct gac aaa ggctgc tct cag tac ttc tat gca gag cat 336 Thr Ile Gly Ser Asp Lys Gly CysSer Gln Tyr Phe Tyr Ala Glu His 100 105 110 ctg tct ctc cac tac ccg ctggag att tct gca gcc tca ggg agg ctg 384 Leu Ser Leu His Tyr Pro Leu GluIle Ser Ala Ala Ser Gly Arg Leu 115 120 125 atg tgt cac ttc aag ctg gtggcc ata gtg ggc tac ctg att cgt ctc 432 Met Cys His Phe Lys Leu Val AlaIle Val Gly Tyr Leu Ile Arg Leu 130 135 140 tca atc aag tcc atc caa atcgaa gcc gac aac tgt gtc act gac tcc 480 Ser Ile Lys Ser Ile Gln Ile GluAla Asp Asn Cys Val Thr Asp Ser 145 150 155 160 ctg acc att tac gac tccctt ttg ccc atc cgg agc agc atc ttg tac 528 Leu Thr Ile Tyr Asp Ser LeuLeu Pro Ile Arg Ser Ser Ile Leu Tyr 165 170 175 aga att tgt gaa ccc acaaga aca tta atg tca ttt gtt tct aca aat 576 Arg Ile Cys Glu Pro Thr ArgThr Leu Met Ser Phe Val Ser Thr Asn 180 185 190 aat ctc atg ttg gtg acattt aag tct cct cat ata cgg agg ctc tca 624 Asn Leu Met Leu Val Thr PheLys Ser Pro His Ile Arg Arg Leu Ser 195 200 205 gga atc cgg gca tat tttgag gtc att cca gaa caa aag tgt gaa aac 672 Gly Ile Arg Ala Tyr Phe GluVal Ile Pro Glu Gln Lys Cys Glu Asn 210 215 220 aca gtg ttg gtc aaa gacatc act ggc ttt gaa ggg aaa att tca agc 720 Thr Val Leu Val Lys Asp IleThr Gly Phe Glu Gly Lys Ile Ser Ser 225 230 235 240 cca tat tac ccg agctac tat cct cca aaa tgc aag tgt acc tgg aaa 768 Pro Tyr Tyr Pro Ser TyrTyr Pro Pro Lys Cys Lys Cys Thr Trp Lys 245 250 255 ttt cag act tct ctatca act ctt ggc ata gca ctg aaa ttc tat aac 816 Phe Gln Thr Ser Leu SerThr Leu Gly Ile Ala Leu Lys Phe Tyr Asn 260 265 270 tat tca ata acc aagaag agt atg aaa ggc tgt gag cat gga tgg tgg 864 Tyr Ser Ile Thr Lys LysSer Met Lys Gly Cys Glu His Gly Trp Trp 275 280 285 gaa att tat gag cacatg tac tgt ggc tcc tac atg gat cat cag aca 912 Glu Ile Tyr Glu His MetTyr Cys Gly Ser Tyr Met Asp His Gln Thr 290 295 300 att ttt cga gtg cccagc cct ctg gtt cac att cag ctc cag tgc agt 960 Ile Phe Arg Val Pro SerPro Leu Val His Ile Gln Leu Gln Cys Ser 305 310 315 320 tca agg ctt tcaggc aag cca ctt ttg gca gaa tat ggc agt tac aac 1008 Ser Arg Leu Ser GlyLys Pro Leu Leu Ala Glu Tyr Gly Ser Tyr Asn 325 330 335 atc agt caa ccctgc cct gtg gga tct ttt aga tgc tcc tcc ggt tta 1056 Ile Ser Gln Pro CysPro Val Gly Ser Phe Arg Cys Ser Ser Gly Leu 340 345 350 tgt gtc cct caggcc cag cgt ggt gat gga gta aat gac tgc ttt gat 1104 Cys Val Pro Gln AlaGln Arg Gly Asp Gly Val Asn Asp Cys Phe Asp 355 360 365 gaa agt gat gaactg ttt tgc gtg agc cct caa cct gcc tgc aat acc 1152 Glu Ser Asp Glu LeuPhe Cys Val Ser Pro Gln Pro Ala Cys Asn Thr 370 375 380 agc tcc ttc aggcag cat ggc cct ctc atc tgt gat ggc ttc agg gac 1200 Ser Ser Phe Arg GlnHis Gly Pro Leu Ile Cys Asp Gly Phe Arg Asp 385 390 395 400 tgt gag aatggc cgg gat gag caa aac tgc act caa agt att cca tgc 1248 Cys Glu Asn GlyArg Asp Glu Gln Asn Cys Thr Gln Ser Ile Pro Cys 405 410 415 aac aac agaact ttt aag tgt ggc aat gat att tgc ttt agg aaa caa 1296 Asn Asn Arg ThrPhe Lys Cys Gly Asn Asp Ile Cys Phe Arg Lys Gln 420 425 430 aat gca aaatgt gat ggg aca gtg gat tgt cca gat gga agt gat gaa 1344 Asn Ala Lys CysAsp Gly Thr Val Asp Cys Pro Asp Gly Ser Asp Glu 435 440 445 gaa ggc tgcacc tgc agc agg agt tcc tcc gcc ctt cac cgc atc atc 1392 Glu Gly Cys ThrCys Ser Arg Ser Ser Ser Ala Leu His Arg Ile Ile 450 455 460 gga ggc acagac acc ctg gag ggg ggt tgg ccg tgg cag gtc agc ctc 1440 Gly Gly Thr AspThr Leu Glu Gly Gly Trp Pro Trp Gln Val Ser Leu 465 470 475 480 cac tttgtt gga tct gcc tac tgt ggt gcc tca gtc atc tcc agg gag 1488 His Phe ValGly Ser Ala Tyr Cys Gly Ala Ser Val Ile Ser Arg Glu 485 490 495 tgg cttctt tct gca gcc cac tgt ttt cat gga aac agg ctg tca gat 1536 Trp Leu LeuSer Ala Ala His Cys Phe His Gly Asn Arg Leu Ser Asp 500 505 510 ccc acacca tgg act gca cac ctc ggg atg tat gtt cag ggg aat gcc 1584 Pro Thr ProTrp Thr Ala His Leu Gly Met Tyr Val Gln Gly Asn Ala 515 520 525 aag tttgtc tcc ccg gtg aga aga att gtg gtc cac gag tac tat aac 1632 Lys Phe ValSer Pro Val Arg Arg Ile Val Val His Glu Tyr Tyr Asn 530 535 540 agt cagact ttt gat tat gat att gct ttg cta cag ctc agt att gcc 1680 Ser Gln ThrPhe Asp Tyr Asp Ile Ala Leu Leu Gln Leu Ser Ile Ala 545 550 555 560 tggcct gag acc ctg aaa cag ctc att cag cca ata tgc att cct ccc 1728 Trp ProGlu Thr Leu Lys Gln Leu Ile Gln Pro Ile Cys Ile Pro Pro 565 570 575 actggt cag aga gtt cgc agt ggg gag aag tgc tgg gta act ggc tgg 1776 Thr GlyGln Arg Val Arg Ser Gly Glu Lys Cys Trp Val Thr Gly Trp 580 585 590 gggcga aga cac gaa gca gat aat aaa ggc tcc ctc gtt ctg cag caa 1824 Gly ArgArg His Glu Ala Asp Asn Lys Gly Ser Leu Val Leu Gln Gln 595 600 605 gcggag gta gag ctc att gat caa acg ctc tgt gtt tcc acc tac ggg 1872 Ala GluVal Glu Leu Ile Asp Gln Thr Leu Cys Val Ser Thr Tyr Gly 610 615 620 atcatc act tct cgg atg ctc tgt gca ggc ata atg tca ggc aag aga 1920 Ile IleThr Ser Arg Met Leu Cys Ala Gly Ile Met Ser Gly Lys Arg 625 630 635 640gat gcc tgc aaa gga gat tcg ggt gga cct tta tct tgt cga aga aaa 1968 AspAla Cys Lys Gly Asp Ser Gly Gly Pro Leu Ser Cys Arg Arg Lys 645 650 655agt gat gga aaa tgg att ttg act ggc att gtt agc tgg gga cat gga 2016 SerAsp Gly Lys Trp Ile Leu Thr Gly Ile Val Ser Trp Gly His Gly 660 665 670tgt gga cga cca aac ttt cct ggt gtt tac aca agg gtg tca aac ttt 2064 CysGly Arg Pro Asn Phe Pro Gly Val Tyr Thr Arg Val Ser Asn Phe 675 680 685gtt ccc tgg att cat aaa tat gtc cct tct ctt ttg taa t tgcaaaaaaa 2114Val Pro Trp Ile His Lys Tyr Val Pro Ser Leu Leu * 690 695 700 aaaaaaaaaaaaaaaa 2130 <210> SEQ ID NO 45 <211> LENGTH: 700 <212> TYPE: PRT <213>ORGANISM: Homo Sapien <400> SEQUENCE: 45 Ile Asn Leu Val Tyr Thr Thr SerAla Phe Ser Lys Phe Tyr Glu Gln 1 5 10 15 Ser Val Val Ala Asp Val SerSer Asn Asn Lys Gly Gly Leu Leu Val 20 25 30 His Phe Trp Ile Val Phe ValMet Pro Arg Ala Lys Gly His Ile Phe 35 40 45 Cys Glu Asp Cys Val Ala AlaIle Leu Lys Asp Ser Ile Gln Thr Ser 50 55 60 Ile Ile Asn Arg Thr Ser ValGly Ser Leu Gln Gly Leu Ala Val Asp 65 70 75 80 Met Asp Ser Val Val LeuAsn Ala Gly Leu Arg Ser Asp Tyr Ser Ser 85 90 95 Thr Ile Gly Ser Asp LysGly Cys Ser Gln Tyr Phe Tyr Ala Glu His 100 105 110 Leu Ser Leu His TyrPro Leu Glu Ile Ser Ala Ala Ser Gly Arg Leu 115 120 125 Met Cys His PheLys Leu Val Ala Ile Val Gly Tyr Leu Ile Arg Leu 130 135 140 Ser Ile LysSer Ile Gln Ile Glu Ala Asp Asn Cys Val Thr Asp Ser 145 150 155 160 LeuThr Ile Tyr Asp Ser Leu Leu Pro Ile Arg Ser Ser Ile Leu Tyr 165 170 175Arg Ile Cys Glu Pro Thr Arg Thr Leu Met Ser Phe Val Ser Thr Asn 180 185190 Asn Leu Met Leu Val Thr Phe Lys Ser Pro His Ile Arg Arg Leu Ser 195200 205 Gly Ile Arg Ala Tyr Phe Glu Val Ile Pro Glu Gln Lys Cys Glu Asn210 215 220 Thr Val Leu Val Lys Asp Ile Thr Gly Phe Glu Gly Lys Ile SerSer 225 230 235 240 Pro Tyr Tyr Pro Ser Tyr Tyr Pro Pro Lys Cys Lys CysThr Trp Lys 245 250 255 Phe Gln Thr Ser Leu Ser Thr Leu Gly Ile Ala LeuLys Phe Tyr Asn 260 265 270 Tyr Ser Ile Thr Lys Lys Ser Met Lys Gly CysGlu His Gly Trp Trp 275 280 285 Glu Ile Tyr Glu His Met Tyr Cys Gly SerTyr Met Asp His Gln Thr 290 295 300 Ile Phe Arg Val Pro Ser Pro Leu ValHis Ile Gln Leu Gln Cys Ser 305 310 315 320 Ser Arg Leu Ser Gly Lys ProLeu Leu Ala Glu Tyr Gly Ser Tyr Asn 325 330 335 Ile Ser Gln Pro Cys ProVal Gly Ser Phe Arg Cys Ser Ser Gly Leu 340 345 350 Cys Val Pro Gln AlaGln Arg Gly Asp Gly Val Asn Asp Cys Phe Asp 355 360 365 Glu Ser Asp GluLeu Phe Cys Val Ser Pro Gln Pro Ala Cys Asn Thr 370 375 380 Ser Ser PheArg Gln His Gly Pro Leu Ile Cys Asp Gly Phe Arg Asp 385 390 395 400 CysGlu Asn Gly Arg Asp Glu Gln Asn Cys Thr Gln Ser Ile Pro Cys 405 410 415Asn Asn Arg Thr Phe Lys Cys Gly Asn Asp Ile Cys Phe Arg Lys Gln 420 425430 Asn Ala Lys Cys Asp Gly Thr Val Asp Cys Pro Asp Gly Ser Asp Glu 435440 445 Glu Gly Cys Thr Cys Ser Arg Ser Ser Ser Ala Leu His Arg Ile Ile450 455 460 Gly Gly Thr Asp Thr Leu Glu Gly Gly Trp Pro Trp Gln Val SerLeu 465 470 475 480 His Phe Val Gly Ser Ala Tyr Cys Gly Ala Ser Val IleSer Arg Glu 485 490 495 Trp Leu Leu Ser Ala Ala His Cys Phe His Gly AsnArg Leu Ser Asp 500 505 510 Pro Thr Pro Trp Thr Ala His Leu Gly Met TyrVal Gln Gly Asn Ala 515 520 525 Lys Phe Val Ser Pro Val Arg Arg Ile ValVal His Glu Tyr Tyr Asn 530 535 540 Ser Gln Thr Phe Asp Tyr Asp Ile AlaLeu Leu Gln Leu Ser Ile Ala 545 550 555 560 Trp Pro Glu Thr Leu Lys GlnLeu Ile Gln Pro Ile Cys Ile Pro Pro 565 570 575 Thr Gly Gln Arg Val ArgSer Gly Glu Lys Cys Trp Val Thr Gly Trp 580 585 590 Gly Arg Arg His GluAla Asp Asn Lys Gly Ser Leu Val Leu Gln Gln 595 600 605 Ala Glu Val GluLeu Ile Asp Gln Thr Leu Cys Val Ser Thr Tyr Gly 610 615 620 Ile Ile ThrSer Arg Met Leu Cys Ala Gly Ile Met Ser Gly Lys Arg 625 630 635 640 AspAla Cys Lys Gly Asp Ser Gly Gly Pro Leu Ser Cys Arg Arg Lys 645 650 655Ser Asp Gly Lys Trp Ile Leu Thr Gly Ile Val Ser Trp Gly His Gly 660 665670 Cys Gly Arg Pro Asn Phe Pro Gly Val Tyr Thr Arg Val Ser Asn Phe 675680 685 Val Pro Trp Ile His Lys Tyr Val Pro Ser Leu Leu 690 695 700<210> SEQ ID NO 46 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Quat: (R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 46 Leu Arg Ala Xaa Gly Arg Ala Xaa 1 5 <210> SEQID NO 47 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificialsequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Xaa is Alanine-therapeuticagent <400> SEQUENCE: 47 Leu Arg Ala Xaa Ala Arg Ala Xaa 1 5 <210> SEQID NO 48 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificialsequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Quat: (R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 48 Leu Arg Ser Xaa Gly Arg Ala Xaa 1 5 <210> SEQID NO 49 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificialsequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Quat: (R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 49 Leu Arg Ser Xaa Ala Arg Ala Xaa 1 5 <210> SEQID NO 50 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificialsequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Isoleucine-therapeutic agent <400> SEQUENCE: 50 Leu Arg Pro Arg Phe LysIle Xaa 1 5 <210> SEQ ID NO 51 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 51 Arg Pro ArgPhe Lys Ile Xaa 1 5 <210> SEQ ID NO 52 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 52Pro Arg Phe Lys Ile Xaa 1 5 <210> SEQ ID NO 53 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 53Leu Arg Ser Lys Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 54 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 54Arg Ser Lys Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 55 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 55Ser Lys Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 56 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 56Leu Arg Pro Arg Phe Arg Ile Xaa 1 5 <210> SEQ ID NO 57 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE:57 Arg Pro Arg Phe Arg Ile Xaa 1 5 <210> SEQ ID NO 58 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE:58 Pro Arg Phe Arg Ile Xaa 1 5 <210> SEQ ID NO 59 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 59Leu Arg Ser Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 60 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 60Arg Ser Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 61 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 61Ser Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 62 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 62 Leu Arg AlaXaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 63 <211> LENGTH: 8 <212> TYPE:PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 63 Leu Arg AlaXaa Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 64 <211> LENGTH: 8 <212> TYPE:PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 64 Leu Arg SerXaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 65 <211> LENGTH: 8 <212> TYPE:PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 65 Leu Arg SerXaa Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 66 <211> LENGTH: 8 <212> TYPE:PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 66Leu Arg Pro Arg Phe Lys Ile Xaa 1 5 <210> SEQ ID NO 67 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE:67 Arg Pro Arg Phe Lys Ile Xaa 1 5 <210> SEQ ID NO 68 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE:68 Pro Arg Phe Lys Ile Xaa 1 5 <210> SEQ ID NO 69 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 69Leu Arg Ser Lys Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 70 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 70Arg Ser Lys Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 71 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: (1)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeutic agent <400>SEQUENCE: 71 Ser Lys Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 72 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Isoleucine-therapeutic agent <400> SEQUENCE: 72 Leu Arg Pro Arg Phe ArgIle Xaa 1 5 <210> SEQ ID NO 73 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 73 Arg Pro ArgPhe Arg Ile Xaa 1 5 <210> SEQ ID NO 74 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 74Pro Arg Phe Arg Ile Xaa 1 5 <210> SEQ ID NO 75 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Alanine-Therapeutic Agent <400> SEQUENCE: 75Leu Arg Ser Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 76 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 76Arg Ser Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 77 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 77Ser Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 78 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is pyroglutamic acid <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 78 Xaa Pro ArgAla Xaa 1 5 <210> SEQ ID NO 79 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is CH3SO2-D-HHT: HHT is hexahydrotyrosol <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 79 Xaa Gly ArgAla Xaa 1 5 <210> SEQ ID NO 80 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is N-p-tosyl-Gly <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 80 Xaa Pro Arg Ala Xaa 1 5 <210> SEQ ID NO 81<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBenzoyl-Val <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 81Xaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 82 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is CH3SO2-D-HHT: HHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 82Xaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 83 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is N-aplha-Z-D-Arg: Z isbenzyloxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 83Xaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 84 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is pyroglutamic acid <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 84 Xaa Gly ArgAla Xaa 1 5 <210> SEQ ID NO 85 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is H-D-Ile <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Alanine- therapeutic agent<400> SEQUENCE: 85 Xaa Pro Arg Ala Xaa 1 5 <210> SEQ ID NO 86 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isCbo-L-(gamma)Glu(alpha-t-BuO): Cbo is carbobenzoxy <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 86 Xaa Arg Ala Ala Xaa 1 5<210> SEQ ID NO 87 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-D-Pro <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400>SEQUENCE: 87 Xaa Phe Arg Ala Xaa 1 5 <210> SEQ ID NO 88 <211> LENGTH: 5<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-Val <220> FEATURE:<221> NAME/KEY: MUTAGEN <222> LOCATION: 5 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 88 Xaa Leu Arg Ala Xaa 1 5<210> SEQ ID NO 89 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Bz-Ile: Bz is benzoyl <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 89 Xaa Glu Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 90<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBz-Ile: Bz is benzoyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeutic agent <400>SEQUENCE: 90 Xaa Xaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 91 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBenzoyl-Pro <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 91Xaa Phe Arg Ala Xaa 1 5 <210> SEQ ID NO 92 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-Phe <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: pipecolinicacid <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 92 Xaa XaaArg Ala Xaa 1 5 <210> SEQ ID NO 93 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is H-D-Val <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Alanine-therapeutic agent<400> SEQUENCE: 93 Xaa Leu Lys Ala Xaa 1 5 <210> SEQ ID NO 94 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isH-D-Nle <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223>OTHER INFORMATION: HHT: HHT is hexahydrotyrosyl <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 94 Xaa Xaa Lys Ala Xaa 1 5<210> SEQ ID NO 95 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is pyroglutamic acid <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 95 Xaa Arg Thr Lys Arg Ala Xaa 1 5 <210> SEQ ID NO96 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isH-Arg <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223>OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 96 Xaa GlnArg Arg Ala Xaa 1 5 <210> SEQ ID NO 97 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Boc-Gln: Boc ist-butoxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 97Xaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 98 <211> LENGTH: 4 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Z-Arg: Z isbenzyloxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:4 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 98Xaa Arg Ala Xaa 1 <210> SEQ ID NO 99 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-HHT: HHT ishexahydrotyrosol <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 99Xaa Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 100 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-CHT: HHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 100Xaa Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 101 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is MeSO2-D-Phe <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 101 Xaa Pro Arg Ala Xaa 1 5<210> SEQ ID NO 102 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is delta-Z-D-Lys: Z is benzyloxycarbonyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 102 Xaa Pro Arg Ala Xaa 1 5<210> SEQ ID NO 103 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is CH3SO2-D-CHA: CHA is cyclohexylalanyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaais But-Arg <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 103Xaa Xaa Ala Xaa 1 <210> SEQ ID NO 104 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 104Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 105 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Ala-therapeutic agent <400> SEQUENCE: 105 ArgArg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 106 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 106Leu Arg Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 107 <211> LENGTH: 5<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 107Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 108 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 108Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 109 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Glycine-therapeutic agent <400> SEQUENCE: 109Leu Arg Arg Gln Ser Arg Gly Xaa 1 5 <210> SEQ ID NO 110 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeutic agent <400>SEQUENCE: 110 Leu Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 111 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: (0)...(0) <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Isoleucine-therapeutic agent <400> SEQUENCE: 111 Arg Arg Gln Ser Arg Xaa1 5 <210> SEQ ID NO 112 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Isoleucine-therapeutic agent <400> SEQUENCE: 112 Leu ArgArg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 113 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: (1)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(Alpha-(3-amidinobenzyl) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 113 Leu Arg Ala Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO114 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 114 Leu Arg Ala Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO115 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 115 Leu Arg Ser Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO116 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 116 Leu Arg Ser Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO117 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 117 Leu Arg Pro Arg Phe Lys Ser Xaa 1 5 <210> SEQID NO 118 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 118 Arg Pro Arg Phe Lys SerXaa 1 5 <210> SEQ ID NO 119 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 119 Pro Arg PheLys Ser Xaa 1 5 <210> SEQ ID NO 120 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 120Leu Arg Ser Lys Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 121 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 121Arg Ser Lys Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 122 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 122Ser Lys Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 123 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 123Leu Arg Pro Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 124 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 124 Arg Pro Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 125 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 125 Pro Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO126 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: (0)...(0) <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 126 Leu Arg Ser Arg Ser ArgSer Xaa 1 5 <210> SEQ ID NO 127 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 127 Arg Ser ArgSer Arg Ser Xaa 1 5 <210> SEQ ID NO 128 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 128Ser Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 129 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 129 Leu Arg Ala Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO130 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 130 Leu Arg Ala Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO131 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 131 Leu Arg Ser Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO132 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 132 Leu Arg Ser Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO133 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 133 Leu Arg Pro Arg Phe Lys Ser Xaa 1 5 <210> SEQID NO 134 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 134 Arg Pro Arg Phe Lys SerXaa 1 5 <210> SEQ ID NO 135 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 135 Pro Arg PheLys Ser Xaa 1 5 <210> SEQ ID NO 136 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 136Leu Arg Ser Lys Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 137 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 137Arg Ser Lys Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 138 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 138Ser Lys Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 139 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 139Leu Arg Pro Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 140 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 140Arg Pro Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 141 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 141Pro Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 142 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 142Leu Arg Ser Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 143 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 143Arg Ser Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 144 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 144Ser Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 145 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is pyroglutamic acid <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 145 Xaa Pro ArgSer Xaa 1 5 <210> SEQ ID NO 146 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is CH3SO2-D-HHT; HHT is hexahydrotyrosyl <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 146 Xaa Gly ArgSer Xaa 1 5 <210> SEQ ID NO 147 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is n-p-tosyl-Gly <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 147 Xaa Pro Arg Ser Xaa 1 5 <210> SEQ ID NO 148<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBenzoyl-Val <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 148Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 149 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is CH3SO2-D-HHT; HHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 149Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 150 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is N-alpha-Z-D-Arg; Z isbenzyloxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 150Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 151 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is pyroglutamic acid <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 151 Xaa Gly ArgSer Xaa 1 5 <210> SEQ ID NO 152 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is H-D-Ile <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 152 Xaa Pro Arg Ser Xaa 1 5 <210> SEQ ID NO 153 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isCbo-L-(gamma)Glu(alpha-t-BuO); Cbo is carbobenzoxy <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 153 Xaa Gly Arg Ser Xaa 1 5<210> SEQ ID NO 154 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-D-Pro <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 154 Xaa Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 155 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-Val <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 155 Xaa Leu ArgSer Xaa 1 5 <210> SEQ ID NO 156 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is Bz-Ile; Bz is benzoyl <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 156 Xaa Glu Gly Arg Ser Xaa 15 <210> SEQ ID NO 157 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Bz-Ile <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 2 <223> OTHER INFORMATION: Xaa is Glu(gamma-OMe) <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 157 Xaa Xaa GlyArg Ser Xaa 1 5 <210> SEQ ID NO 158 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is benzoyle-Pro <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 158 Xaa Phe Arg Ser Xaa 1 5<210> SEQ ID NO 159 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-D-Phe <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 2 <223> OTHER INFORMATION: Xaa is Pip is pipecolinic acid<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic acid <400> SEQUENCE: 159 Xaa Xaa ArgSer Xaa 1 5 <210> SEQ ID NO 160 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is H-D-Val <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeutic acid<400> SEQUENCE: 160 Xaa Leu Lys Ser Xaa 1 5 <210> SEQ ID NO 161 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isH-D-Nle <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223>OTHER INFORMATION: Xaa is HHT: hexahydrotyrosyl <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Xaa isleucine-therapeutic agent <400> SEQUENCE: 161 Xaa Xaa Lys Ser Xaa 1 5<210> SEQ ID NO 162 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is pyroglutamic acid <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 162 Xaa Arg Thr Lys Arg Ser Xaa 1 5 <210> SEQ IDNO 163 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-Arg <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 163 Xaa Gln Arg Arg Ser Xaa 1 5 <210> SEQ ID NO 164 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBoc-Gln <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Xaa is Leucine-therapeutic agent <400> SEQUENCE: 164Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 165 <211> LENGTH: 4 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Z-Arg: Z isbenzyloxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:4 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 165Xaa Arg Ser Xaa 1 <210> SEQ ID NO 166 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-HHT: HHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 166Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 167 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-CHT: CHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 167Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 168 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is MeSO2-dPhe <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 168 Xaa Pro Arg Ser Xaa 1 5<210> SEQ ID NO 169 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is delta-Z-D-Lys: Z is benzyloxycarbonyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 169 Xaa Pro Arg Ser Xaa 1 5<210> SEQ ID NO 170 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is CH3SO2-D-CHA: CHA is cyclohexylalanyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaais But-Arg <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 170Xaa Xaa Ser Xaa 1 <210> SEQ ID NO 171 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 171Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 172 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 172Arg Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 173 <211> LENGTH: 8<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:8 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 173Leu Arg Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 174 <211> LENGTH: 5<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 174Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 175 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 175Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 176 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 176Leu Arg Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 177 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 177Leu Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 178 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 178Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 179 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 179Leu Arg Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 180 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 180Arg Gln Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 181 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 181Arg Gln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 182 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 182Arg Gln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 183 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 183Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 184 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 184Arg Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 185 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 185Arg Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 186 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 186Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 187 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 187Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 188 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 188Gln Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 189 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 189Gln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 190 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 190Gln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 191 <211> LENGTH: 9 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(Alpha-(3-amidinobenzyl)<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 191 Leu Arg AlaXaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 192 <211> LENGTH: 9 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 192 Leu Arg AlaXaa Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 193 <211> LENGTH: 9 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 193 Leu Arg SerXaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 194 <211> LENGTH: 9 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Quat: (R)-Glu(alpha-(3-amidinobenzyl))<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 194 Leu Arg SerXaa Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 195 <211> LENGTH: 9 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 195Leu Arg Pro Arg Phe Lys Ser Ser Xaa 1 5 <210> SEQ ID NO 196 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 196 Arg Pro Arg Phe Lys Ser Ser Xaa 1 5 <210> SEQID NO 197 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 197 Pro Arg Phe Lys Ser SerXaa 1 5 <210> SEQ ID NO 198 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 198 Leu Arg SerLys Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 199 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 199Arg Ser Lys Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 200 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 200Ser Lys Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 201 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:9 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 201Leu Arg Pro Arg Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 202 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 202 Arg Pro Arg Phe Arg Ser Ser Xaa 1 5 <210> SEQID NO 203 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 203 Pro Arg Phe Arg Ser SerXaa 1 5 <210> SEQ ID NO 204 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 204 Leu Arg SerArg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 205 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 205Arg Ser Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 206 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 206Ser Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 207 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 4 <223> OTHER INFORMATION: Xaa is Quat:(R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 9 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 207 Leu Arg Ala Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 208 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Quat: (R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 208 Leu Arg Ala Xaa Ala Arg Ser Ser Xaa 1 5 <210>SEQ ID NO 209 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Quat: (R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 209 Leu Arg Ser Xaa Gly Arg Ser Ser Xaa 1 5 <210>SEQ ID NO 210 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Quat: (R)-Glu(alpha-(3-amidinobenzyl)) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 210 Leu Arg Ser Xaa Ala Arg Ser Ser Xaa 1 5 <210>SEQ ID NO 211 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 211 Leu Arg Pro Arg Phe LysSer Ser Xaa 1 5 <210> SEQ ID NO 212 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 212Arg Pro Arg Phe Lys Ser Ser Xaa 1 5 <210> SEQ ID NO 213 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 213Pro Arg Phe Lys Ser Ser Xaa 1 5 <210> SEQ ID NO 214 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:9 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 214Leu Arg Ser Lys Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 215 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 215 Arg Ser Lys Ser Arg Ser Ser Xaa 1 5 <210> SEQID NO 216 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 216 Ser Lys Ser Arg Ser SerXaa 1 5 <210> SEQ ID NO 217 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 217 Leu Arg ProArg Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 218 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 218Arg Pro Arg Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 219 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 219Pro Arg Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 220 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:9 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 220Leu Arg Ser Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 221 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 221 Arg Ser Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQID NO 222 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 222 Ser Arg Ser Arg Ser SerXaa 1 5 <210> SEQ ID NO 223 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is pyroglutamic acid <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 223 Xaa Pro Arg Ser Ser Xaa 15 <210> SEQ ID NO 224 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is CH3SO2-D-HHT; HHT is hexahydrotyrosyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 224 Xaa Gly Arg Ser Ser Xaa 15 <210> SEQ ID NO 225 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is n-p-tosyl-Gly <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 225 Xaa Pro Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 226<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBenzoyl-Val <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 226Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 227 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is CH3SO2-D-HHT; HHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 227Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 228 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is N-alpha-Z-D-Arg; Z isbenzyloxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 228Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 229 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is pyroglutamic acid <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 229 Xaa Gly ArgSer Ser Xaa 1 5 <210> SEQ ID NO 230 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-Ile <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 230 Xaa Pro Arg Ser Ser Xaa 15 <210> SEQ ID NO 231 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Cbo-L-(gamma)Glu(alpha-t-BuO); Cbo is carbobenzoxy<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 231 Xaa Gly ArgSer Ser Xaa 1 5 <210> SEQ ID NO 232 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-Pro <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 232 Xaa Phe Arg Ser Ser Xaa 15 <210> SEQ ID NO 233 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-D-Val <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 233 Xaa Leu Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 234 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBz-Ile; Bz is benzoyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 234 Xaa Glu Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 235 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBz-Ile <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223>OTHER INFORMATION: Xaa is Glu(gamma-OMe) <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 235 Xaa Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 236 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is benzoyle-Pro <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 236 Xaa Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 237<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isH-D-Phe <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223>OTHER INFORMATION: Xaa is Pip is pipecolinic acid <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic acid <400> SEQUENCE: 237 Xaa Xaa Arg Ser Ser Xaa 1 5<210> SEQ ID NO 238 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-D-Val <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic acid <400>SEQUENCE: 238 Xaa Leu Lys Ser Ser Xaa 1 5 <210> SEQ ID NO 239 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isH-D-Nle <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223>OTHER INFORMATION: Xaa is HHT: hexahydrotyrosyl <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Xaa isleucine-therapeutic agent <400> SEQUENCE: 239 Xaa Xaa Lys Ser Ser Xaa 15 <210> SEQ ID NO 240 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is pyroglutamic acid <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 240 Xaa Arg Thr Lys Arg Ser Ser Xaa 1 5 <210> SEQID NO 241 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is H-Arg <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 241 Xaa Gln Arg Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 242 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isBoc-Gln <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223>OTHER INFORMATION: Xaa is Leucine-therapeutic agent <400> SEQUENCE: 242Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 243 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Z-Arg: Z isbenzyloxycarbonyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 243Xaa Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 244 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-HHT: HHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 244Xaa Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 245 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is H-D-CHT: CHT ishexahydrotyrosyl <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 245Xaa Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 246 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is MeSO2-dPhe <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 246 Xaa Pro Arg Ser Ser Xaa 15 <210> SEQ ID NO 247 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is delta-Z-D-Lys: Z is benzyloxycarbonyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 247 Xaa Pro Arg Ser Ser Xaa 15 <210> SEQ ID NO 248 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is CH3SO2-D-CHA: CHA is cyclohexylalanyl <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaais But-Arg <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 248Xaa Xaa Ser Ser Xaa 1 5 <210> SEQ ID NO 249 <211> LENGTH: 7 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 249Arg Gln Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 250 <211> LENGTH: 8<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:8 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 250Arg Arg Gln Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 251 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:9 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 251Leu Arg Arg Gln Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 252 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 252 Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 253<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 253 Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO254 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 254 Leu Arg Arg Gln Ser Arg Ser Ser Xaa 1 5 <210>SEQ ID NO 255 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 255 Leu Arg Arg Gln Ser ArgSer Xaa 1 5 <210> SEQ ID NO 256 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 256 Arg Arg GlnSer Arg Ser Xaa 1 5 <210> SEQ ID NO 257 <211> LENGTH: 9 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 257Leu Arg Arg Gln Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 258 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 258 Arg Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 259 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 259 Arg Gln Ala Arg Ser SerXaa 1 5 <210> SEQ ID NO 260 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic acid <400> SEQUENCE: 260 Arg Gln PheArg Ser Ser Xaa 1 5 <210> SEQ ID NO 261 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 261Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 262 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 262Arg Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 263 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 263Arg Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 264 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 264Arg Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 265 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 265Gln Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 266 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 266Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 267 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: leucine-therapeutic agent <400> SEQUENCE: 267Gln Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 268 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 268Gln Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 269 <211> LENGTH: 816 <212>TYPE: DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (1)...(816) <223> OTHER INFORMATION: Nucleotide sequenceencoding MTSP25, including MTSP25 protease domain <220> FEATURE: <221>NAME/KEY: misc_feature <222> LOCATION: (248)...(270) <223> OTHERINFORMATION: Transmembrane domain encompasses amino acids 248-270 at theC-terminus of the trypsin-like serine protease domain (amino acids1-237) <400> SEQUENCE: 269 att ata ggg ggc acc gaa gca caa gct ggc gcatgg ccg tgg gtg gtg 48 Ile Ile Gly Gly Thr Glu Ala Gln Ala Gly Ala TrpPro Trp Val Val 1 5 10 15 agc ctg cag att aaa tat ggc cgt gtt ctt gttcat gta tgt ggg gga 96 Ser Leu Gln Ile Lys Tyr Gly Arg Val Leu Val HisVal Cys Gly Gly 20 25 30 acc cta gtg aga gag agg tgg gtc ctc aca gct gcccac tgc act aaa 144 Thr Leu Val Arg Glu Arg Trp Val Leu Thr Ala Ala HisCys Thr Lys 35 40 45 gac gct agc gat cct tta atg tgg aca gct gtg att ggaact aat aat 192 Asp Ala Ser Asp Pro Leu Met Trp Thr Ala Val Ile Gly ThrAsn Asn 50 55 60 ata cat gga cgc tat cct cat acc aag aag ata aaa att aaagca atc 240 Ile His Gly Arg Tyr Pro His Thr Lys Lys Ile Lys Ile Lys AlaIle 65 70 75 80 att att cat cca aac ttc att ttg gaa tct tat gta aat gatatt gca 288 Ile Ile His Pro Asn Phe Ile Leu Glu Ser Tyr Val Asn Asp IleAla 85 90 95 ctt ttt cac tta aaa aaa gca gtg agg tat aat gac tat att cagcct 336 Leu Phe His Leu Lys Lys Ala Val Arg Tyr Asn Asp Tyr Ile Gln Pro100 105 110 att tgc cta cct ttt gat gtt ttc caa atc ctg gac gga aac acaaag 384 Ile Cys Leu Pro Phe Asp Val Phe Gln Ile Leu Asp Gly Asn Thr Lys115 120 125 tgt ttt ata agt ggc tgg gga aga aca aaa gaa gaa ggt aac gctaca 432 Cys Phe Ile Ser Gly Trp Gly Arg Thr Lys Glu Glu Gly Asn Ala Thr130 135 140 aat att tta caa gat gca gaa gtg cat tat att tct cga gag atgtgt 480 Asn Ile Leu Gln Asp Ala Glu Val His Tyr Ile Ser Arg Glu Met Cys145 150 155 160 aat tct gag agg agt tat ggg gga ata att cct aac act tcattt tgt 528 Asn Ser Glu Arg Ser Tyr Gly Gly Ile Ile Pro Asn Thr Ser PheCys 165 170 175 gca ggt gat gaa gat gga gct ttt gat act tgc agg ggt gacagt ggg 576 Ala Gly Asp Glu Asp Gly Ala Phe Asp Thr Cys Arg Gly Asp SerGly 180 185 190 gga cca tta atg tgc tac tta cca gaa tat aaa aga ttt tttgta atg 624 Gly Pro Leu Met Cys Tyr Leu Pro Glu Tyr Lys Arg Phe Phe ValMet 195 200 205 gga att acc agt tac gga cat ggc tgt ggt cga aga ggt tttcct ggt 672 Gly Ile Thr Ser Tyr Gly His Gly Cys Gly Arg Arg Gly Phe ProGly 210 215 220 gtc tat att ggg cca tcc ttc tac caa aag tgg ctg aca gagcat ttc 720 Val Tyr Ile Gly Pro Ser Phe Tyr Gln Lys Trp Leu Thr Glu HisPhe 225 230 235 240 ttc cat gca agc act caa ggc ata ctt act ata aat atttta cgt ggc 768 Phe His Ala Ser Thr Gln Gly Ile Leu Thr Ile Asn Ile LeuArg Gly 245 250 255 cag atc ctc ata gct tta tgt ttt gtc atc tta cta gcaaca aca taa 816 Gln Ile Leu Ile Ala Leu Cys Phe Val Ile Leu Leu Ala ThrThr * 260 265 270 <210> SEQ ID NO 270 <211> LENGTH: 271 <212> TYPE: PRT<213> ORGANISM: Homo Sapien <400> SEQUENCE: 270 Ile Ile Gly Gly Thr GluAla Gln Ala Gly Ala Trp Pro Trp Val Val 1 5 10 15 Ser Leu Gln Ile LysTyr Gly Arg Val Leu Val His Val Cys Gly Gly 20 25 30 Thr Leu Val Arg GluArg Trp Val Leu Thr Ala Ala His Cys Thr Lys 35 40 45 Asp Ala Ser Asp ProLeu Met Trp Thr Ala Val Ile Gly Thr Asn Asn 50 55 60 Ile His Gly Arg TyrPro His Thr Lys Lys Ile Lys Ile Lys Ala Ile 65 70 75 80 Ile Ile His ProAsn Phe Ile Leu Glu Ser Tyr Val Asn Asp Ile Ala 85 90 95 Leu Phe His LeuLys Lys Ala Val Arg Tyr Asn Asp Tyr Ile Gln Pro 100 105 110 Ile Cys LeuPro Phe Asp Val Phe Gln Ile Leu Asp Gly Asn Thr Lys 115 120 125 Cys PheIle Ser Gly Trp Gly Arg Thr Lys Glu Glu Gly Asn Ala Thr 130 135 140 AsnIle Leu Gln Asp Ala Glu Val His Tyr Ile Ser Arg Glu Met Cys 145 150 155160 Asn Ser Glu Arg Ser Tyr Gly Gly Ile Ile Pro Asn Thr Ser Phe Cys 165170 175 Ala Gly Asp Glu Asp Gly Ala Phe Asp Thr Cys Arg Gly Asp Ser Gly180 185 190 Gly Pro Leu Met Cys Tyr Leu Pro Glu Tyr Lys Arg Phe Phe ValMet 195 200 205 Gly Ile Thr Ser Tyr Gly His Gly Cys Gly Arg Arg Gly PhePro Gly 210 215 220 Val Tyr Ile Gly Pro Ser Phe Tyr Gln Lys Trp Leu ThrGlu His Phe 225 230 235 240 Phe His Ala Ser Thr Gln Gly Ile Leu Thr IleAsn Ile Leu Arg Gly 245 250 255 Gln Ile Leu Ile Ala Leu Cys Phe Val IleLeu Leu Ala Thr Thr 260 265 270 <210> SEQ ID NO 271 <211> LENGTH: 8<212> TYPE: PRT <213> ORGANISM: amino acids 401-407 of SEQ ID No. 97 inWO 02/00860 <400> SEQUENCE: 271 Arg Lys His Leu Pro Arg Pro Ala 1 5<210> SEQ ID NO 272 <211> LENGTH: 228 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: alternativePD1 of MTSP12 <400> SEQUENCE: 272 Ile Val Gly Gly Met Glu Ala Ser ProGly Glu Phe Pro Trp Gln Ala 1 5 10 15 Ser Leu Arg Glu Asn Lys Glu HisPhe Cys Gly Ala Ala Ile Ile Asn 20 25 30 Ala Arg Trp Leu Val Ser Ala AlaHis Cys Phe Asn Glu Phe Gln Asp 35 40 45 Pro Thr Lys Trp Val Ala Tyr ValGly Ala Thr Tyr Leu Ser Gly Ser 50 55 60 Glu Ala Ser Thr Val Arg Ala GlnVal Val Gln Ile Val Lys His Pro 65 70 75 80 Leu Tyr Asn Ala Asp Thr AlaAsp Phe Asp Val Ala Val Leu Glu Leu 85 90 95 Thr Ser Pro Leu Pro Phe GlyArg His Ile Gln Pro Val Cys Leu Pro 100 105 110 Ala Ala Thr His Ile PhePro Pro Ser Lys Lys Cys Leu Ile Ser Gly 115 120 125 Trp Gly Tyr Leu LysGlu Asp Phe Leu Arg Lys His Leu Pro Arg Pro 130 135 140 Ala Val Lys ProGly Val Leu Gln Lys Ala Thr Val Glu Leu Leu Asp 145 150 155 160 Gln AlaLeu Cys Ala Ser Leu Tyr Gly His Ser Leu Thr Asp Arg Met 165 170 175 ValCys Ala Gly Tyr Leu Asp Gly Lys Val Asp Ser Cys Gln Gly Asp 180 185 190Ser Gly Gly Pro Leu Val Cys Glu Glu Pro Ser Gly Arg Phe Ser Leu 195 200205 Ala Gly Ile Val Ser Trp Gly Ile Gly Cys Ala Glu Ala Arg Arg Pro 210215 220 Gly Val Tyr Ala 225 <210> SEQ ID NO 273 <211> LENGTH: 804 <212>TYPE: DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (1)...(804) <223> OTHER INFORMATION: Nucleotide sequenceencoding MTSP20, including MTSP20 protease domain <400> SEQUENCE: 273aca gca ggt ccc cag gca gga gca ccc tcc cca tgg ccc tgg gag gcc 48 ThrAla Gly Pro Gln Ala Gly Ala Pro Ser Pro Trp Pro Trp Glu Ala 1 5 10 15agg ctg atg cac cag gga cag ctg gcc tgt ggc gga gcc ctg gtg tca 96 ArgLeu Met His Gln Gly Gln Leu Ala Cys Gly Gly Ala Leu Val Ser 20 25 30 gaggag acg gtg cta act gtt gcc cac tgc ttc att ggg cgc cag gcc 144 Glu GluThr Val Leu Thr Val Ala His Cys Phe Ile Gly Arg Gln Ala 35 40 45 cca gaggaa tgg agc gta ggg ctg ggg acc aga ccg gag gag tgg ggc 192 Pro Glu GluTrp Ser Val Gly Leu Gly Thr Arg Pro Glu Glu Trp Gly 50 55 60 ctg aag cagctc atc ctg cat gga gcc tac acc cac cct gag ggg ggc 240 Leu Lys Gln LeuIle Leu His Gly Ala Tyr Thr His Pro Glu Gly Gly 65 70 75 80 tac gac atggcc ctc ctg ctg ctg gcc cag cct gtg aca ctg gga gcc 288 Tyr Asp Met AlaLeu Leu Leu Leu Ala Gln Pro Val Thr Leu Gly Ala 85 90 95 agc ctg cgg cccctc tgc ctg ccc tat cct gac cac cac ctg cct gat 336 Ser Leu Arg Pro LeuCys Leu Pro Tyr Pro Asp His His Leu Pro Asp 100 105 110 ggg gag cgt ggctgg gtt ctg gga cgg gcc cgc cca gga gca ggc atc 384 Gly Glu Arg Gly TrpVal Leu Gly Arg Ala Arg Pro Gly Ala Gly Ile 115 120 125 agc tcc ctc cagaca gtg ccc gtg acc ctc ctg ggg cct agg gcc tgc 432 Ser Ser Leu Gln ThrVal Pro Val Thr Leu Leu Gly Pro Arg Ala Cys 130 135 140 agc cgg ctg catgca gct cct ggg ggt gat ggc agc cct att ctg ccg 480 Ser Arg Leu His AlaAla Pro Gly Gly Asp Gly Ser Pro Ile Leu Pro 145 150 155 160 ggg atg gtgtgt acc agt gct gtg ggt gag ctg ccc agc tgt gag ggc 528 Gly Met Val CysThr Ser Ala Val Gly Glu Leu Pro Ser Cys Glu Gly 165 170 175 ctg tct ggggca cca ctg gtg cat gag gtg agg ggc aca tgg ttc ctg 576 Leu Ser Gly AlaPro Leu Val His Glu Val Arg Gly Thr Trp Phe Leu 180 185 190 gcc ggg ctgcac agc ttc gga gat gct tgc caa ggc ccc gcc agg ccg 624 Ala Gly Leu HisSer Phe Gly Asp Ala Cys Gln Gly Pro Ala Arg Pro 195 200 205 gcg gtc ttcacc gcg ctc cct gcc tat gag gac tgg gtc agc agt ttg 672 Ala Val Phe ThrAla Leu Pro Ala Tyr Glu Asp Trp Val Ser Ser Leu 210 215 220 gac tgg caggtc tac ttc gcc gag gaa cca gag ccc gag gct gag cct 720 Asp Trp Gln ValTyr Phe Ala Glu Glu Pro Glu Pro Glu Ala Glu Pro 225 230 235 240 gga agctgc ctg gcc aac atg agt atg tgg ccc cgg ggc ctc ctg cca 768 Gly Ser CysLeu Ala Asn Met Ser Met Trp Pro Arg Gly Leu Leu Pro 245 250 255 aac cctgcc tct cca gga ccc ttc tct ctc cag tga 804 Asn Pro Ala Ser Pro Gly ProPhe Ser Leu Gln * 260 265 <210> SEQ ID NO 274 <211> LENGTH: 267 <212>TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 274 Thr Ala GlyPro Gln Ala Gly Ala Pro Ser Pro Trp Pro Trp Glu Ala 1 5 10 15 Arg LeuMet His Gln Gly Gln Leu Ala Cys Gly Gly Ala Leu Val Ser 20 25 30 Glu GluThr Val Leu Thr Val Ala His Cys Phe Ile Gly Arg Gln Ala 35 40 45 Pro GluGlu Trp Ser Val Gly Leu Gly Thr Arg Pro Glu Glu Trp Gly 50 55 60 Leu LysGln Leu Ile Leu His Gly Ala Tyr Thr His Pro Glu Gly Gly 65 70 75 80 TyrAsp Met Ala Leu Leu Leu Leu Ala Gln Pro Val Thr Leu Gly Ala 85 90 95 SerLeu Arg Pro Leu Cys Leu Pro Tyr Pro Asp His His Leu Pro Asp 100 105 110Gly Glu Arg Gly Trp Val Leu Gly Arg Ala Arg Pro Gly Ala Gly Ile 115 120125 Ser Ser Leu Gln Thr Val Pro Val Thr Leu Leu Gly Pro Arg Ala Cys 130135 140 Ser Arg Leu His Ala Ala Pro Gly Gly Asp Gly Ser Pro Ile Leu Pro145 150 155 160 Gly Met Val Cys Thr Ser Ala Val Gly Glu Leu Pro Ser CysGlu Gly 165 170 175 Leu Ser Gly Ala Pro Leu Val His Glu Val Arg Gly ThrTrp Phe Leu 180 185 190 Ala Gly Leu His Ser Phe Gly Asp Ala Cys Gln GlyPro Ala Arg Pro 195 200 205 Ala Val Phe Thr Ala Leu Pro Ala Tyr Glu AspTrp Val Ser Ser Leu 210 215 220 Asp Trp Gln Val Tyr Phe Ala Glu Glu ProGlu Pro Glu Ala Glu Pro 225 230 235 240 Gly Ser Cys Leu Ala Asn Met SerMet Trp Pro Arg Gly Leu Leu Pro 245 250 255 Asn Pro Ala Ser Pro Gly ProPhe Ser Leu Gln 260 265 <210> SEQ ID NO 275 <211> LENGTH: 699 <212>TYPE: DNA <213> ORGANISM: Homo Sapien <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (1)...(699) <223> OTHER INFORMATION: Nucleotide sequenceencoding MTSP22, including MTSP22 protease domain <400> SEQUENCE: 275att gtg aat gga aaa agc tcc ctg gag ggg gca tgg cca tgg cag gcc 48 IleVal Asn Gly Lys Ser Ser Leu Glu Gly Ala Trp Pro Trp Gln Ala 1 5 10 15agc atg caa tgg aaa ggc cgt cac tac tgt gga gcc tct ctg atc agc 96 SerMet Gln Trp Lys Gly Arg His Tyr Cys Gly Ala Ser Leu Ile Ser 20 25 30 agcagg tgg cta tta tct gca gct cac tgc ttt gct aag aaa aat aat 144 Ser ArgTrp Leu Leu Ser Ala Ala His Cys Phe Ala Lys Lys Asn Asn 35 40 45 tca aaagat tgg act gtc aac ttt gga gtt gta gta aat aaa cca tat 192 Ser Lys AspTrp Thr Val Asn Phe Gly Val Val Val Asn Lys Pro Tyr 50 55 60 atg aca cggaaa gtc caa aac att att ttt cat gaa aat tat agc agt 240 Met Thr Arg LysVal Gln Asn Ile Ile Phe His Glu Asn Tyr Ser Ser 65 70 75 80 cct ggg cttcat gat gat att gcc ctt gtg cag ctt gct gaa gaa gtt 288 Pro Gly Leu HisAsp Asp Ile Ala Leu Val Gln Leu Ala Glu Glu Val 85 90 95 tct ttt aca gagtac att cgt aag att tgt ctt cct gaa gcc aaa atg 336 Ser Phe Thr Glu TyrIle Arg Lys Ile Cys Leu Pro Glu Ala Lys Met 100 105 110 aag ctc tca gaaaat gac aat gtt gta gtt aca ggt tgg gga aca ctt 384 Lys Leu Ser Glu AsnAsp Asn Val Val Val Thr Gly Trp Gly Thr Leu 115 120 125 tat atg aat ggttca ttt cca gtg ata ctt caa gaa gcc ttt ttg aag 432 Tyr Met Asn Gly SerPhe Pro Val Ile Leu Gln Glu Ala Phe Leu Lys 130 135 140 att att gac aacaaa att tgc aat gcc tca tat gca tac tct ggc tta 480 Ile Ile Asp Asn LysIle Cys Asn Ala Ser Tyr Ala Tyr Ser Gly Leu 145 150 155 160 gtg act gataca atg tta tgt gct gga ttt atg tca gga gaa gct gat 528 Val Thr Asp ThrMet Leu Cys Ala Gly Phe Met Ser Gly Glu Ala Asp 165 170 175 gca tgt cagaat gat tct ggt gga cca cta gct tac cct gat tcc aga 576 Ala Cys Gln AsnAsp Ser Gly Gly Pro Leu Ala Tyr Pro Asp Ser Arg 180 185 190 aat atc tggcat ctt gtt gga ata gta agc tgg ggt gat gga tgt ggt 624 Asn Ile Trp HisLeu Val Gly Ile Val Ser Trp Gly Asp Gly Cys Gly 195 200 205 aaa aag aataag cca ggt gtc tat act cga gtg act tct tat cgc aat 672 Lys Lys Asn LysPro Gly Val Tyr Thr Arg Val Thr Ser Tyr Arg Asn 210 215 220 tgg att acatcc aag act gga ctc tga 699 Trp Ile Thr Ser Lys Thr Gly Leu * 225 230<210> SEQ ID NO 276 <211> LENGTH: 232 <212> TYPE: PRT <213> ORGANISM:Homo Sapien <400> SEQUENCE: 276 Ile Val Asn Gly Lys Ser Ser Leu Glu GlyAla Trp Pro Trp Gln Ala 1 5 10 15 Ser Met Gln Trp Lys Gly Arg His TyrCys Gly Ala Ser Leu Ile Ser 20 25 30 Ser Arg Trp Leu Leu Ser Ala Ala HisCys Phe Ala Lys Lys Asn Asn 35 40 45 Ser Lys Asp Trp Thr Val Asn Phe GlyVal Val Val Asn Lys Pro Tyr 50 55 60 Met Thr Arg Lys Val Gln Asn Ile IlePhe His Glu Asn Tyr Ser Ser 65 70 75 80 Pro Gly Leu His Asp Asp Ile AlaLeu Val Gln Leu Ala Glu Glu Val 85 90 95 Ser Phe Thr Glu Tyr Ile Arg LysIle Cys Leu Pro Glu Ala Lys Met 100 105 110 Lys Leu Ser Glu Asn Asp AsnVal Val Val Thr Gly Trp Gly Thr Leu 115 120 125 Tyr Met Asn Gly Ser PhePro Val Ile Leu Gln Glu Ala Phe Leu Lys 130 135 140 Ile Ile Asp Asn LysIle Cys Asn Ala Ser Tyr Ala Tyr Ser Gly Leu 145 150 155 160 Val Thr AspThr Met Leu Cys Ala Gly Phe Met Ser Gly Glu Ala Asp 165 170 175 Ala CysGln Asn Asp Ser Gly Gly Pro Leu Ala Tyr Pro Asp Ser Arg 180 185 190 AsnIle Trp His Leu Val Gly Ile Val Ser Trp Gly Asp Gly Cys Gly 195 200 205Lys Lys Asn Lys Pro Gly Val Tyr Thr Arg Val Thr Ser Tyr Arg Asn 210 215220 Trp Ile Thr Ser Lys Thr Gly Leu <210> SEQ ID NO 277 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 277 Gly SerGly Arg Ser Xaa 1 5 <210> SEQ ID NO 278 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Xaa is Leucine-therapeutic Agent <220> FEATURE:<223> OTHER INFORMATION: conjugate <400> SEQUENCE: 278 Gly Ser Gly ArgSer Xaa 1 5 <210> SEQ ID NO 279 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 279 Gly Ser Gly Arg Ser Ser Xaa 15 <210> SEQ ID NO 280 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 280 Gly Ser Gly Arg Xaa 1 5 <210>SEQ ID NO 281 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: AMIDATION <222> LOCATION: 6 <221>NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaa is4-Guanidino-phenylglycine <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 281 Gly Ser Gly Xaa Ser Leu 1 5 <210> SEQ IDNO 282 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Cyclohexylamine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 282 Gly Ser Gly Arg Ser Ser Xaa 15 <210> SEQ ID NO 283 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 283 Gly Ser Gly Arg Ala Ser Xaa 15 <210> SEQ ID NO 284 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 284 Gly Ser Gly Arg Ser Xaa 1 5<210> SEQ ID NO 285 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: (0)...(0) <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223>OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 285 Gly Thr Gly Arg Ser Xaa 1 5<210> SEQ ID NO 286 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Succinyl-BAlanine <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nle-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 286Ala Thr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 287 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 287Gly Thr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 288 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Homoserine<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Nle-Therapeutic AgentNle <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 288 Gly Xaa Gly Arg Ser Xaa 1 5 <210> SEQ IDNO 289 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is D Serine <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 289 Gly Xaa Ala Arg Ser Xaa1 5 <210> SEQ ID NO 290 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 290 Gly Ser Ala Arg Ser Xaa 1 5<210> SEQ ID NO 291 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 291 Gly Ser Ala Arg Ser SerXaa 1 5 <210> SEQ ID NO 292 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 292 Gly Ser Ala Arg Ser Ser Xaa 15 <210> SEQ ID NO 293 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 293 Gly Ser Ala Arg Ala Ser Xaa 15 <210> SEQ ID NO 294 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 294 Val Ser Gly Arg Ser Xaa 1 5<210> SEQ ID NO 295 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 295 Val Ser Gly Arg Ala Xaa 1 5<210> SEQ ID NO 296 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 296 Val Ser Gly Arg Ala Ser Xaa 15 <210> SEQ ID NO 297 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 297 Val Ser Gly Arg Ser Ser Xaa 15 <210> SEQ ID NO 298 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Alanine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 298 Val Ser Ala Arg Met Xaa 1 5<210> SEQ ID NO 299 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Xaa is Nle <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeutic Agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 299 Val SerAla Arg Xaa Xaa 1 5 <210> SEQ ID NO 300 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 300 Val Ser Ala Arg Ser Xaa1 5 <210> SEQ ID NO 301 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 301 Val Ser Ala Arg Ser Xaa 1 5<210> SEQ ID NO 302 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is S-Methylcysteine <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: dValine-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 302Xaa Pro Gly Arg Val Xaa 1 5 <210> SEQ ID NO 303 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isS-Methylcysteine <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Valine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 303 Xaa Pro Gly Arg Val Xaa 1 5<210> SEQ ID NO 304 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is S-Methylcysteine <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 304Xaa Pro Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 305 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isS-Methylcysteine <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 305 Xaa Pro Gly Arg Ser Xaa 1 5<210> SEQ ID NO 306 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is S-Methylcysteine <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 306Xaa Pro Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 307 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isS-Methylcysteine <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 307 Xaa Pro Ala Arg Ala Ser Xaa 15 <210> SEQ ID NO 308 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is t-Butyl Glycine <221> NAME/KEY: MOD_RES<222> LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 308Xaa Pro Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 309 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 3 <223> OTHER INFORMATION: Xaa is D Serine <221>NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Alanine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 309 Arg Gly Xaa Ala Arg Ser Xaa 1 5 <210> SEQID NO 310 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Alanine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 310 Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQID NO 311 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 311 Arg Gly Ser Gly Arg Ala Xaa 1 5 <210> SEQID NO 312 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 312 Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQID NO 313 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 313 Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 314<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <221>NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 314 Arg Gly Ser Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 315<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <221>NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 315 Arg Gly Ser Gly Arg Ser Ser Xaa 1 5 <210>SEQ ID NO 316 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 316 Arg Gly Ser Gly Arg Ser Xaa 15 <210> SEQ ID NO 317 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 317 Arg Gly Ser Gly Arg SerSer Xaa 1 5 <210> SEQ ID NO 318 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 318 Arg Gly Ser Ala Arg SerXaa 1 5 <210> SEQ ID NO 319 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 319 Arg Gly Ser Ala Arg SerSer Xaa 1 5 <210> SEQ ID NO 320 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Nva-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 320 Arg Gly Ser Ala Arg Ser Xaa 15 <210> SEQ ID NO 321 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Nva-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 321 Arg Gly Ser Ala Arg Ser SerXaa 1 5 <210> SEQ ID NO 322 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 322 Arg Gly Ser Ala Arg Ser Xaa 15 <210> SEQ ID NO 323 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2<223> OTHER INFORMATION: Xaa is S-MethylCysteine <221> NAME/KEY: MOD_RES<222> LOCATION: 7 <223> OTHER INFORMATION: Valine-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 323Arg Xaa Pro Gly Arg Val Xaa 1 5 <210> SEQ ID NO 324 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa isS-Methylcysteine <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Valine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 324 Arg Xaa Pro Gly Arg Val Xaa 15 <210> SEQ ID NO 325 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2<223> OTHER INFORMATION: Xaa is S-Methylcysteine <221> NAME/KEY: MOD_RES<222> LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic Agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 325Arg Xaa Pro Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 326 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic Agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 326 Arg LeuPro Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 327 <211> LENGTH: 7 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: VARIANT <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 327 Arg Val Pro Gly Arg SerXaa 1 5 <210> SEQ ID NO 328 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: VARIANT <222> LOCATION: 8 <223> OTHERINFORMATION: dLeucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 328 Arg Val Pro Gly Arg Ser Xaa 15 <210> SEQ ID NO 329 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2<223> OTHER INFORMATION: Xaa is Nle <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Leucine-therapeutic Agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 329 Arg XaaPro Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 330 <211> LENGTH: 7 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is t-Butylglycine <221>NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 330 Arg Xaa Pro Ala Arg Ser Xaa 1 5 <210> SEQID NO 331 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 331 Arg Leu Pro Ala Arg Ser Xaa 1 5 <210> SEQID NO 332 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 332 Arg Val Pro Ala Arg Ser Xaa 1 5 <210> SEQID NO 333 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is Nle <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223>OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 333 Arg Xaa Pro Ala Arg Ser Xaa 15 <210> SEQ ID NO 334 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 334 Ile Val Ser Gly Arg Ala Xaa 15 <210> SEQ ID NO 335 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 335 Ile Val Ser Gly Arg Ser SerXaa 1 5 <210> SEQ ID NO 336 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 336 Ile Val Ser Gly Arg Ala SerXaa 1 5 <210> SEQ ID NO 337 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Alanine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 337 Ile Val Ser Ala Arg Met Xaa 15 <210> SEQ ID NO 338 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Xaa is Nle <221> NAME/KEY: MOD_RES <222>LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeutic Agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 338 Ile ValSer Ala Arg Xaa Xaa 1 5 <210> SEQ ID NO 339 <211> LENGTH: 7 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 339 Ile Val Ser Ala Arg SerXaa 1 5 <210> SEQ ID NO 340 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Nle-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 340 Ile Val Ser Ala Arg Ser Xaa 15 <210> SEQ ID NO 341 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 341 Ile Val Ser Ala Arg Ser SerXaa 1 5 <210> SEQ ID NO 342 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: VARIANT <222> LOCATION: 8 <223> OTHERINFORMATION: dLeucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 342 Leu Arg Gly Ser Gly Arg SerXaa 1 5 <210> SEQ ID NO 343 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 343 Leu Arg Gly Ser Gly Arg SerXaa 1 5 <210> SEQ ID NO 344 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 344 Leu Arg Gly Ser Gly Arg SerSer Xaa 1 5 <210> SEQ ID NO 345 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 345 Leu Arg Gly Ser Gly ArgSer Ser Xaa 1 5 <210> SEQ ID NO 346 <211> LENGTH: 9 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 346 Leu Arg Gly Ser Ala ArgSer Ser Xaa 1 5 <210> SEQ ID NO 347 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 347 Leu Arg Gly Ser Ala ArgSer Xaa 1 5 <210> SEQ ID NO 348 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 348 Leu Arg Gly Ser Ala ArgSer Ser Xaa 1 5 <210> SEQ ID NO 349 <211> LENGTH: 9 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Nva-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 349 Leu Arg Gly Ser Ala ArgSer Ser Xaa 1 5 <210> SEQ ID NO 350 <211> LENGTH: 9 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 350 Leu Arg Gly Ser Ala ArgSer Ser Xaa 1 5 <210> SEQ ID NO 351 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9<223> OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 351 Val Ile Val Ser Gly ArgAla Xaa 1 5 <210> SEQ ID NO 352 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 352 Val Ile Val Ser Ala Arg SerXaa 1 5 <210> SEQ ID NO 353 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 353 Val Ile Val Ser Gly Arg SerSer Xaa 1 5 <210> SEQ ID NO 354 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Alanine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 354 Val Ile Val Ser Ala Arg MetXaa 1 5 <210> SEQ ID NO 355 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Xaa is Nle <221> NAME/KEY: MOD_RES <222>LOCATION: 8 <223> OTHER INFORMATION: Alanine-therapeutic Agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 355 Val IleVal Ser Ala Arg Xaa Xaa 1 5 <210> SEQ ID NO 356 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 8 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 356 Val IleVal Ser Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 357 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 8 <223> OTHER INFORMATION: dCyclohexylalanine-therapeuticagent <220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE:357 Val Ile Val Ser Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 358 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 358 Val Ile Val Ser Ala Arg SerXaa 1 5 <210> SEQ ID NO 359 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 359 Val Ile Val Ser Ala ArgSer Ser Xaa 1 5 <210> SEQ ID NO 360 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 3 <223> OTHER INFORMATION: Xaa is S-methylcysteine <221>NAME/KEY: MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION:Valine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 360 Arg Arg Xaa Pro Gly Arg Val Xaa 1 5 <210>SEQ ID NO 361 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHERINFORMATION: Xaa is Nva <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223>OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 361 Arg Arg Xaa Pro Ala Arg SerXaa 1 5 <210> SEQ ID NO 362 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 362 Ser Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 363 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 363 Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 364 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 364 Ser Gly Arg Ser Ser Ser Xaa 1 5 <210> SEQID NO 365 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 365 Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 366 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: dNva-therapeuticagent <220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE:366 Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 367 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Nva-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 367 Ser GlyArg Ser Xaa 1 5 <210> SEQ ID NO 368 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: (0)...(0) <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Hexylglycine-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 368Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 369 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 369 Ser GlyArg Ser Xaa 1 5 <210> SEQ ID NO 370 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Homocyclohexylalanine-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 370 Ser GlyArg Ser Xaa 1 5 <210> SEQ ID NO 371 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 371 Ser Ala Arg Ser Ser Xaa1 5 <210> SEQ ID NO 372 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 372 Ser Ala Arg Ser Ser Xaa 1 5<210> SEQ ID NO 373 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 373 Ser Ser Arg Ser Xaa 1 5 <210>SEQ ID NO 374 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Abu-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 374 Thr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 375 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticAgent <220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE:375 Thr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 376 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Nva-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 376 Thr GlyArg Ser Xaa 1 5 <210> SEQ ID NO 377 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 377 Thr Gly Arg Ser Xaa 1 5<210> SEQ ID NO 378 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Hexylglycine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 378 Thr Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 379 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 379 Thr Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 380 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Homocyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 380 Thr Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 381 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Abu-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 381 Thr Gly Arg Thr Xaa 1 5 <210> SEQ ID NO 382 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHER INFORMATION: Xaais Homoserine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 382 Thr Gly Arg Xaa Xaa 1 5 <210>SEQ ID NO 383 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHERINFORMATION: Xaa is Abu <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 383 Thr Gly Arg Xaa Xaa 1 5 <210>SEQ ID NO 384 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHERINFORMATION: Xaa is Abu <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Nva-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 384 Thr Gly Arg Xaa Xaa 1 5 <210>SEQ ID NO 385 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHERINFORMATION: Xaa is 4-Guanidinophenylalanine <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 385 Thr GlyXaa Ser Xaa 1 5 <210> SEQ ID NO 386 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 3 <223> OTHER INFORMATION: Xaa is4-Guanidinophenylalanine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <220> FEATURE:<223> OTHER INFORMATION: conjugate <400> SEQUENCE: 386 Thr Gly Xaa SerXaa 1 5 <210> SEQ ID NO 387 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:3 <223> OTHER INFORMATION: Xaa is 4-Guanidinophenylalanine <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHERINFORMATION: Xaa is Abu <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Nva-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 387 Thr Gly Xaa Xaa Xaa 1 5 <210>SEQ ID NO 388 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHERINFORMATION: Xaa is Alloc <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 388 Thr Gly Xaa Ser Xaa 1 5<210> SEQ ID NO 389 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 389 Thr Gly Lys Ser Xaa 1 5 <210>SEQ ID NO 390 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHERINFORMATION: Xaa is Homoarginine <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 390 Thr Gly Xaa Ser Xaa 1 5<210> SEQ ID NO 391 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is N-homoserine <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 391 Xaa GlyArg Ser Xaa 1 5 <210> SEQ ID NO 392 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isN-Methyloxycarbonyl threonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 392 Xaa Gly Arg Ser Xaa 1 5<210> SEQ ID NO 393 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Phenylsulfonyl threonine<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 393 Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 394 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Methoxyethylcarbonyl threonine <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 394Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 395 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxydiethoxyacetyl threonine <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 395 Xaa Gly Arg Ser Xaa 1 5<210> SEQ ID NO 396 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is 4-Oxo-pentanoyl threonine<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 396 Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 397 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is 2-Benzo[1,3]dioxo1-5-yl acetylthreonine <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 397 Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 398 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is 2-Pyridin-2-yl-acetyl threonine <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 398Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 399 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is Benzoylacetylthreonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 399 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 400 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is 2-Hydroxy-3-phenyl propionylacetyl threonine<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugateSEQUENCE: 400 Thr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 401 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaais Methoxyacetylthreonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 401 Xaa Gly Arg Ser Xaa 1 5<210> SEQ ID NO 402 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Phenylacetyl threonine <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 402 Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 403 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is 3-Methoxypropionyl threonine <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 403 Thr GlyArg Ser Xaa 1 5 <210> SEQ ID NO 404 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxyethoxyacetyl threonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 404 Thr Gly Arg Ser Xaa 1 5<210> SEQ ID NO 405 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is 1-Carboxybutanoyl threonine<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 405 Thr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 406 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Carboxybenzyl threonine <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 406 Xaa GlyArg Ser Xaa 1 5 <210> SEQ ID NO 407 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isEthoxycarbonylthreonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 407 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 408 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is BAlanine <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 408 Xaa ThrGly Arg Ser Xaa 1 5 <210> SEQ ID NO 409 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is Pent-4-ynoylthreonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 409 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 410 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is Naphthaacetyl threonine <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 410Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 411 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isIsobutyloxycarbonyl threonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjuagate <400> SEQUENCE: 411 Xaa Gly Arg Ser Xaa 15 <210> SEQ ID NO 412 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa is Hydroxyacetyl threonine<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 412 Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 413 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Methoxycarboxylpropanoyl threonine <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 413Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 414 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is N,N-dimethylglycine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 414 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 415 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is Succinyl threonine <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 415 Xaa GlyArg Ser Xaa 1 5 <210> SEQ ID NO 416 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is Formylthreonine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 416 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 417 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 417 Thr Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 418 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHER INFORMATION: Xaais 4-Guanidinophenylalanine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 418 Thr Ala Xaa Ser Xaa 1 5<210> SEQ ID NO 419 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4<223> OTHER INFORMATION: Xaa is Abu <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Nva-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 419 Thr AlaArg Xaa Xaa 1 5 <210> SEQ ID NO 420 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Abu-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 420 Thr Ala Arg Ser Xaa 1 5<210> SEQ ID NO 421 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Abu-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 421 Thr Ala Arg Thr Xaa 1 5 <210>SEQ ID NO 422 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is Serine methyl ester <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 422 Thr XaaArg Ser Xaa 1 5 <210> SEQ ID NO 423 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Homoserine <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 423 Thr Xaa Arg Ser Xaa 1 5 <210> SEQ ID NO 424 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaais 1-Methyl histidine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 424 Thr Xaa Arg Ser Xaa 1 5 <210>SEQ ID NO 425 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is 3-Methyl histidine <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 425 Thr XaaArg Ser Xaa 1 5 <210> SEQ ID NO 426 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 426 Thr His Arg Ser Xaa 1 5<210> SEQ ID NO 427 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2<223> OTHER INFORMATION: Xaa is MeGlycine <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 427 Thr XaaArg Ser Xaa 1 5 <210> SEQ ID NO 428 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Nva <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 428Thr Xaa Arg Ser Xaa 1 5 <210> SEQ ID NO 429 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Nle <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 429Thr Xaa Arg Ser Xaa 1 5 <210> SEQ ID NO 430 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Cyclohexyl alanine-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 430 Thr AlaArg Ser Xaa 1 5 <210> SEQ ID NO 431 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Abu <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Nle-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 431Thr Xaa Arg Ser Xaa 1 5 <210> SEQ ID NO 432 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is 4,4-Dimethylthreonine<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 432 Xaa Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 433 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaais Homoserine <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Nle-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 433 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 434 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1,4 <223> OTHERINFORMATION: Xaa is Homoserine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Cyclohexyl alanine-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 434 Xaa GlyArg Xaa Xaa 1 5 <210> SEQ ID NO 435 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is Homoserine <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 435 Xaa Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 436 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Homoserine <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 436 Xaa GlyArg Thr Xaa 1 5 <210> SEQ ID NO 437 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 1 <223> OTHER INFORMATION: Xaa is Homoserine <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 437 Xaa Ala Arg Ser Xaa 1 5 <210>SEQ ID NO 438 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Nle-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION: conjugate<400> SEQUENCE: 438 Asn Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 439 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticAgent <220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE:439 Tyr Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 440 <211> LENGTH: 5<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent<220> FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 440Tyr Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 441 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <220> FEATURE: <223>OTHER INFORMATION: conjugate <400> SEQUENCE: 441 Gln Gly Arg Ser Ser Xaa1 5 <210> SEQ ID NO 442 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Nva-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 442 Gln Gly Arg Ser Ser Xaa 1 5<210> SEQ ID NO 443 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is N-homoserine <221> NAME/KEY: MOD_RES<222> LOCATION: 4 <223> OTHER INFORMATION: Nle-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 443 Xaa ArgSer Xaa 1 <210> SEQ ID NO 444 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:1 <223> OTHER INFORMATION: Xaa is N-homoserine <221> NAME/KEY: MOD_RES<222> LOCATION: 4 <223> OTHER INFORMATION: Nva-therapeutic agent <220>FEATURE: <223> OTHER INFORMATION: conjugate <400> SEQUENCE: 444 Xaa ArgSer Xaa 1 <210> SEQ ID NO 445 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <221> NAME/KEY: BLOCKED <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic Agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 445 Gln Gly Arg Ser Xaa 1 5 <210>SEQ ID NO 446 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 446 Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 447 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 447 Gln Gly Arg Ala Ser Xaa 1 5 <210> SEQ IDNO 448 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic Agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 448 Asn Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 449 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Nleucine-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 449 Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 450 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Nvaline-therapeutic agent <220> FEATURE: <223> OTHER INFORMATION:conjugate <400> SEQUENCE: 450 Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ IDNO 451 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <220> FEATURE: <223> OTHERINFORMATION: conjugate <400> SEQUENCE: 451 Gln Gly Arg Ser Ser Xaa 1 5<210> SEQ ID NO 452 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Allyl-therapeutic agent <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: conjugate <220>FEATURE: <223> OTHER INFORMATION: Xaa is dSerine <400> SEQUENCE: 452 GlnGly Arg Ser Xaa Xaa 1 5 <210> SEQ ID NO 453 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Allyl-therapeutic agent <400> SEQUENCE: 453 GlnGly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 454 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 454 Gln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 455 <211> LENGTH:6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 455 Gln Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 456<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 456 Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 457<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nva-therapeutic agent<400> SEQUENCE: 457 Gln Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 458<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 458 Gln Ser Arg SerSer Xaa 1 5 <210> SEQ ID NO 459 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 459 Gln Ser ArgSer Ser Xaa 1 5 <210> SEQ ID NO 460 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 460Gln Thr Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 461 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2<223> OTHER INFORMATION: Xaa is Aib <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 461 Gln Xaa Arg SerSer Xaa 1 5 <210> SEQ ID NO 462 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is Aib <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 462 Gln Xaa Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 463 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: (0)...(0) <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Abu<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 463 GlnXaa Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 464 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2<223> OTHER INFORMATION: Xaa is Abu <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 464 Gln Xaa Arg Ser Ser Xaa 1 5 <210> SEQ ID NO465 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa isCyclohexylalanine <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 465 Gln Xaa Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 466 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 466 Gln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 467<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 467 Gln Phe Arg Ser Ser Xaa 1 5 <210> SEQ ID NO468 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 468 Gln Tyr Arg Ser Ser Xaa 1 5 <210> SEQ ID NO469 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 469 Arg Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 470<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 470 Arg Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO471 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 471 Arg Gly Arg SerSer Xaa 1 5 <210> SEQ ID NO 472 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 472 ArgGly Arg Ser Xaa 1 5 <210> SEQ ID NO 473 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 473Arg Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 474 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 474Arg Ala Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 475 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 475Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 476 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 476Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 477 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 477 Arg Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 478 <211> LENGTH:6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 6 <223> OTHER INFORMATION: Cyclohexylalanine-therapeuticagent <400> SEQUENCE: 478 Arg Ser Arg Ser Ser Xaa 1 5 <210> SEQ ID NO479 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 479 Arg Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 480<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 480 Arg Phe Arg SerXaa 1 5 <210> SEQ ID NO 481 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 481 Tyr Gly ArgSer Ser Xaa 1 5 <210> SEQ ID NO 482 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is S-Dioxomethionine <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 482 Xaa Ser Arg Ser Xaa 1 5<210> SEQ ID NO 483 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: conjugate<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is Methoxycarbonyl-(alpha-(3-cyanobenzyl) ) glutamicacid-delta-methyl ester <220> FEATURE: <221> NAME/KEY: AMIDATION <222>LOCATION: 5 <400> SEQUENCE: 483 Xaa Gly Arg Ser Leu 1 5 <210> SEQ ID NO484 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha- (3-amidinobenzyl) ) glutamic acid -delta-methylester <220> FEATURE: <221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400>SEQUENCE: 484 Xaa Gly Arg Ser Leu 1 5 <210> SEQ ID NO 485 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl- (alpha-(3-amidinobenzyl)) glutamic acid <220> FEATURE:<221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400> SEQUENCE: 485 Xaa GlyArg Ser Leu 1 5 <210> SEQ ID NO 486 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha-(3-Methylbenzyl) )glutamic acid -delta-methylester <220> FEATURE: <221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400>SEQUENCE: 486 Xaa Gly Arg Ser Leu 1 5 <210> SEQ ID NO 487 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl- (alpha-(3-methylbenzyl)) glutamic acid <220> FEATURE:<221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400> SEQUENCE: 487 Xaa GlyArg Ser Leu 1 5 <210> SEQ ID NO 488 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha-(3-cyanobenzyl) ) glutamic acid-delta-methylester <220> FEATURE: <221> NAME/KEY: AMIDATION <222> LOCATION: 6 <400>SEQUENCE: 488 Xaa Gly Arg Ser Ser Leu 1 5 <210> SEQ ID NO 489 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha-(3-methylbenzyl) )glutamic acid -delta-methylester <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 489 Xaa GlyArg Ser Xaa 1 5 <210> SEQ ID NO 490 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha-(3-cyanobenzyl) ) glutamic acid -delta-methylester <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223>OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 490 Xaa GlyArg Ser Xaa 1 5 <210> SEQ ID NO 491 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 491Arg Gln Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 492 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 492Arg Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 493 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 493 ArgGln Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 494 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nva-therapeutic agent <400> SEQUENCE: 494 ArgGln Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 495 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Phenylalanine-therapeutic agent <400> SEQUENCE:495 Arg Gln Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 496 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: dLeucine-therapeutic agent <400> SEQUENCE:496 Arg Gln Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 497 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 497Arg Gln Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 498 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: dNle-therapeutic agent <400> SEQUENCE: 498 ArgGln Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 499 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 499 ArgGln Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 500 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nva-therapeutic agent <400> SEQUENCE: 500 ArgGln Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 501 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 501 Arg Gln Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 502 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Phenylalanine-therapeutic agent <400> SEQUENCE: 502 Arg Gln Gly Arg AlaXaa 1 5 <210> SEQ ID NO 503 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: leucine-therapeutic agent <400> SEQUENCE: 503 Arg Asn GlyArg Ser Xaa 1 5 <210> SEQ ID NO 504 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 504 ArgAsn Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 505 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 505Arg Gln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 506 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 506 ArgGln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 507 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nva-therapeutic agent <400> SEQUENCE: 507 ArgGln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 508 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 508 Arg Gln Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 509 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 509 Arg Gln Ala ArgSer Ser Xaa 1 5 <210> SEQ ID NO 510 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 510 ArgGln Ala Arg Thr Xaa 1 5 <210> SEQ ID NO 511 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 511Arg Gln Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 512 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 512 ArgGln Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 513 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nva-therapeutic agent <400> SEQUENCE: 513 ArgGln Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 514 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 514 Arg Gln Ala Arg Ala Xaa 1 5 <210> SEQ ID NO 515 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 515 Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO516 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 516 Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 517<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nle-therapeutic agent<400> SEQUENCE: 517 Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 518<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 518 Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO519 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 519 Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO520 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nva-therapeutic agent<400> SEQUENCE: 520 Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 521<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 521 Arg Gln Ser ArgAla Xaa 1 5 <210> SEQ ID NO 522 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 522 Arg Gln SerArg Ser Ser Xaa 1 5 <210> SEQ ID NO 523 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 523Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 524 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: dNle-therapeutic agent <400> SEQUENCE: 524 ArgGln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 525 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 525 ArgGln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 526 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nva-therapeutic agent <400> SEQUENCE: 526 ArgGln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 527 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Allylglycine-therapeutic agent <400> SEQUENCE:527 Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 528 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 528 Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 529 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nle <400> SEQUENCE:529 Arg Gln Ser Arg Thr Xaa 1 5 <210> SEQ ID NO 530 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 530Arg Gln Thr Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 531 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 531Arg Gln Thr Arg Ser Xaa 1 5 <210> SEQ ID NO 532 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 532 ArgAsn Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 533 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 533Arg Gln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 534 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: dNle-therapeutic agent <400> SEQUENCE: 534 ArgGln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 535 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nva-therapeutic agent <400> SEQUENCE: 535 ArgGln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 536 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 536 ArgGln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 537 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Cyclohexylalanine-therapeutic agent <400>SEQUENCE: 537 Arg Gln Phe Arg Ser Xaa 1 5 <210> SEQ ID NO 538 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 538 Arg Gln Phe Arg Ala Xaa 1 5 <210> SEQ ID NO539 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nle-therapeutic agent<400> SEQUENCE: 539 Arg Gln Phe Arg Ala Xaa 1 5 <210> SEQ ID NO 540<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Nva-therapeutic agent<400> SEQUENCE: 540 Arg Gln Phe Arg Ala Xaa 1 5 <210> SEQ ID NO 541<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Cyclohexylalanine-therapeutic agent <400> SEQUENCE: 541 Arg Gln Phe ArgAla Xaa 1 5 <210> SEQ ID NO 542 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Nle-therapeutic agent <400> SEQUENCE: 542 Gln Ser Arg SerSer Xaa 1 5 <210> SEQ ID NO 543 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 543 Arg Arg GlnSer Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 544 <211> LENGTH: 7 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 544Arg Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 545 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 545Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 546 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 546 ArgGly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 547 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Nle-therapeutic agent <400> SEQUENCE: 547 ArgGly Ser Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 548 <211> LENGTH: 8 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 548Arg Gly Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 549 <211> LENGTH: 8<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 549 Ile Val Ser Gly Arg Ala Ser Xaa 1 5 <210> SEQ ID NO 550<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 9 <223> OTHER INFORMATION:Isoleucine-therapeutic agent <400> SEQUENCE: 550 Leu Arg Arg Gln Ser ArgSer Ser Xaa 1 5 <210> SEQ ID NO 551 <211> LENGTH: 8 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 8<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 551Leu Arg Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 552 <211> LENGTH: 5<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 552Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 553 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 553Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 554 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Glycine-therapeutic agent <400> SEQUENCE: 554Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 555 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 555Arg Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 556 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 556Arg Gln Ser Arg Ala Xaa 1 5 <210> SEQ ID NO 557 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Alalnine-therapeutic agent <400> SEQUENCE: 557Arg Gln Ser Arg Ser Xaa 1 5 <210> SEQ ID NO 558 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 558Arg Gln Ser Arg Ser Ala Xaa 1 5 <210> SEQ ID NO 559 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 559Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 560 <211> LENGTH: 5<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:5 <223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 560Ser Gly Arg Ala Xaa 1 5 <210> SEQ ID NO 561 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 561Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 562 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 562Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 563 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 563Ser Gly Arg Ala Ser Xaa 1 5 <210> SEQ ID NO 564 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Glycine-therapeutic agent <400> SEQUENCE: 564Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 565 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Glycine-therapeutic agent <400> SEQUENCE: 565Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 566 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 566Ser Gly Arg Ser Gly Xaa 1 5 <210> SEQ ID NO 567 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Glycine-therapeutic agent <400> SEQUENCE: 567Ser Gly Arg Ser Gly Xaa 1 5 <210> SEQ ID NO 568 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Glycine-therapeutic agent <400> SEQUENCE: 568Gly Thr Gly Arg Ser Gly Xaa 1 5 <210> SEQ ID NO 569 <211> LENGTH: 6<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:2 <223> OTHER INFORMATION: Xaa is D- Serine <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 569 Gly Xaa Ala Arg Ser Xaa 15 <210> SEQ ID NO 570 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: conjugate<220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHERINFORMATION: Xaa is D-Serine <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeutic agent<400> SEQUENCE: 570 Arg Gly Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 571<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 571 Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO572 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 572 Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ IDNO 573 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 573 Leu Arg Gly Ser Gly ArgSer Xaa 1 5 <210> SEQ ID NO 574 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 4 <223> OTHERINFORMATION: Xaa is D-Serine <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 8 <223> OTHER INFORMATION: Alanine-therapeutic agent<400> SEQUENCE: 574 Leu Arg Gly Xaa Ala Arg Ser Xaa 1 5 <210> SEQ ID NO575 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isS-Methylcysteine <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:6 <223> OTHER INFORMATION: Valine-therapeutic agent <400> SEQUENCE: 575Xaa Pro Gly Arg Val Xaa 1 5 <210> SEQ ID NO 576 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is S-Methylcysteine <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Valine-therapeutic agent <400> SEQUENCE: 576 Xaa Pro Gly Arg Val Xaa 1 5<210> SEQ ID NO 577 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: conjugate<220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is S-Methylcysteine <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Valine-therapeuticagent <400> SEQUENCE: 577 Arg Xaa Pro Gly Arg Val Xaa 1 5 <210> SEQ IDNO 578 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 3 <223> OTHER INFORMATION: Xaais S-Methylcysteine <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 8 <223> OTHER INFORMATION: Valine-therapeutic agent <400>SEQUENCE: 578 Arg Arg Xaa Pro Gly Arg Val Xaa 1 5 <210> SEQ ID NO 579<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 579 Val Ser Ala Arg Met Xaa 1 5 <210> SEQ ID NO580 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 580 Ile Val Ser Ala Arg Met Xaa 1 5 <210> SEQ IDNO 581 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 581 Val Ile Val Ser Ala ArgMet Xaa 1 5 <210> SEQ ID NO 582 <211> LENGTH: 8 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Xaa is Nle <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 8 <223> OTHER INFORMATION: Alanine-therapeutic agent <400>SEQUENCE: 582 Val Ile Val Ser Ala Arg Xaa Xaa 1 5 <210> SEQ ID NO 583<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Xaa is Nle <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Alanine-therapeutic agent <400> SEQUENCE: 583 Val Ser AlaArg Xaa Xaa 1 5 <210> SEQ ID NO 584 <211> LENGTH: 7 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Xaa is Nle <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 7 <223> OTHER INFORMATION: Alanine-therapeuticagent <400> SEQUENCE: 584 Ile Val Ser Ala Arg Xaa Xaa 1 5 <210> SEQ IDNO 585 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION:Leucine-therapeutic agent <400> SEQUENCE: 585 Gly Ser Gly Arg Ser Xaa 15 <210> SEQ ID NO 586 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: conjugate<220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 586 Gly Ser GlyArg Ser Ser Xaa 1 5 <210> SEQ ID NO 587 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 587Gly Ser Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 588 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 588Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 589 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 589Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 590 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 590Ser Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 591 <211> LENGTH: 7 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 7<223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 591Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 592 <211> LENGTH: 8<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:8 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 592Arg Gly Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 593 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:7 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 593Arg Gly Ser Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 594 <211> LENGTH: 8<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:8 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 594Leu Arg Gly Ser Gly Arg Ser Xaa 1 5 <210> SEQ ID NO 595 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION<222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION:9 <223> OTHER INFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 595Leu Arg Gly Ser Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO 596 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 596 Leu Arg Gly Ser Ala Arg Ser Xaa 1 5 <210> SEQID NO 597 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: conjugate <220>FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE:<221> NAME/KEY: MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Alanine-therapeutic agent <400> SEQUENCE: 597 Leu Arg Arg Gln Ser ArgAla Xaa 1 5 <210> SEQ ID NO 598 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223>OTHER INFORMATION: Xaa is N-Methylsulfonyl-alpha-cyclohexyl-D- Alanine<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHERINFORMATION: Xaa is Abu <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeutic agent <400>SEQUENCE: 598 Xaa Xaa Arg Ser Xaa 1 5 <210> SEQ ID NO 599 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES<222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeutic agent<400> SEQUENCE: 599 Arg Ala Arg Ser Xaa 1 5 <210> SEQ ID NO 600 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa siAlpha-Cyclohexyl-D-alanine <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 2 <223> OTHER INFORMATION: Abu <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 5 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 600 Xaa Xaa Arg Ser Xaa 1 5 <210> SEQ ID NO 601<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isAlpha-Cyclohexyl-D-Alanine <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 2 <223> OTHER INFORMATION: Abu <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 601 Xaa Xaa Arg Ser Ser Xaa 1 5 <210> SEQ ID NO602 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 6 <223> OTHER INFORMATION: Leucine-therapeuticagent <400> SEQUENCE: 602 Gln Gly Arg Ser Ser Xaa 1 5 <210> SEQ ID NO603 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: conjugate <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-D-homophenylalanine <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is 4Hyp <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 603 Xaa Xaa ArgSer Ser Xaa 1 5 <210> SEQ ID NO 604 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha)-3-methylbenzyl glutamic acid -delta-methyl ester<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 604 Xaa Gly ArgSer Xaa 1 5 <210> SEQ ID NO 605 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222> LOCATION: 1<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1 <223> OTHERINFORMATION: Xaa is D-cyclohexylalanine <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is 4Hyp <220>FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 5 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 605 Xaa Xaa ArgSer Ser Xaa 1 5 <210> SEQ ID NO 606 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: 1 <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 1<223> OTHER INFORMATION: Xaa is D-Clohexylalanine <220> FEATURE: <221>NAME/KEY: MOD_RES <222> LOCATION: 2 <223> OTHER INFORMATION: Xaa is Abu<220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: 6 <223> OTHERINFORMATION: Leucine-therapeutic agent <400> SEQUENCE: 606 Xaa Xaa ArgSer Ser Xaa 1 5 <210> SEQ ID NO 607 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: conjugate <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha-(3-cyanobenzyl)) glutamic acid -delta-methylester <220> FEATURE: <221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400>SEQUENCE: 607 Xaa Gly Arg Ser Leu 1 5 <210> SEQ ID NO 608 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha- (3-amidinobenzyl)) glutamic acid -delta-methylester <220> FEATURE: <221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400>SEQUENCE: 608 Xaa Gly Arg Ser Leu 1 5 <210> SEQ ID NO 609 <211> LENGTH:5 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: conjugate <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 1 <223> OTHER INFORMATION: Xaa isMethoxycarbonyl-(alpha- (3-amidinobenzyl)) glutamic acid <220> FEATURE:<221> NAME/KEY: AMIDATION <222> LOCATION: 5 <400> SEQUENCE: 609 Xaa GlyArg Ser Leu 1 5 <210> SEQ ID NO 610 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Conjugate <220> FEATURE: <221> NAME/KEY: ACETYLATION <222>LOCATION: (0)...(0) <220> FEATURE: <221> NAME/KEY: MOD_RES <222>LOCATION: 6 <223> OTHER INFORMATION: Isoleucine-therapeutic agent <400>SEQUENCE: 610 Arg Arg Gln Ser Arg Xaa 1 5 <210> SEQ ID NO 611 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Conjugate <220> FEATURE: <221>NAME/KEY: ACETYLATION <222> LOCATION: 1 <220> FEATURE: <221> NAME/KEY:MOD_RES <222> LOCATION: 8 <223> OTHER INFORMATION:Isoleucine-therapeutic agent <400> SEQUENCE: 611 Leu Arg Arg Gln Ser ArgAla Xaa 1 5

What is claimed is:
 1. A conjugate, comprising a therapeutic agent and apeptidic substrate linked thereto optionally via a linker, wherein thepeptidic substrate is proteolytically cleaved by a cell surface proteaseor a soluble, released or shed form thereof, to liberate the therapeuticagent, wherein the conjugate is not substantially cleaved by plasmin orprostate specific antigen (PSA).
 2. The conjugate of claim 1, whereinthe liberated therapeutic agent is active.
 3. The conjugate of claim 1,wherein cleavage liberates the therapeutic agent in a form that requiresfurther processing for activation.
 4. The conjugate of claim 1 thatcomprises the components: (peptidic substrate)_(s), (Linker)_(q), and(therapeutic agent)_(t); wherein at least one peptidic substrate moietyis linked with or without a linker to at least one therapeutic agent, sis 1 to 6, q is 0 to t, and t is 1 to 6, wherein a cell surface proteasethat cleaves the peptidic substrate(s) results in delivery of thetherapeutic agent to the cell.
 5. The conjugate of claim 1, wherein thepeptidic substrate comprises one amino acid or more, wherein, uponproteolytic cleavage of the conjugate, the resulting therapeutic agentis active or in a form that, upon further processing, is active.
 6. Theconjugate of claim 1, wherein the cell surface protease is a serineprotease.
 7. The conjugate of claim 1, wherein the cell surface proteaseis a type II transmembrane serine protease (MTSP) or an endotheliase. 8.The conjugate of claim 1, wherein the cell surface protease is selectedfrom endotheliase 1, endotheliase 2, MTSP1, MTSP3, MTSP4, MTSP6, MTSP7,MTSP9, MTSP10, MTSP12, MTSP20, MTSP22, MTSP25, corin, enterokinase,human airway trypsin-like protease (HAT), TMPRSS2, hepsin,urokinase-type plasminogen activator (uPA), and TMPRSS4.
 9. Theconjugate of claim 1, wherein the cell surface protease comprises apolypeptide selected from the group consisting of a polypeptidecomprising the sequence of amino acids set forth in any of SEQ ID Nos.2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 29, 31, 33, 35, 37, 39,41, 43, 45, 270, 272, 274 and 276; a polypeptide encoded by a sequenceof nucleotides that hybridizes under conditions of high stringency tothe sequence of nucleotides set forth in any of SEQ ID Nos 1, 3, 5, 7,9, 11, 13, 15, 17, 19, 21, 23, 25, 28, 30, 32, 34, 36, 38, 40, 42, 44,269, 273 and 275; a polypeptide that comprises a sequence of amino acidshaving at least about 40% sequence identity with the sequence of aminoacids set forth in SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,24, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 270, 272, 274 and 276; and apolypeptide encoded by a splice variant of the sequence of nucleotidesset forth in any of SEQ ID Nos. 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,24, 26, 29, 31, 33, 35, 37, 39, 41, 43, 45, 270, 272, 274 and
 276. 10.The conjugate of claim 1, wherein the therapeutic agent is a toxin, asmall organic molecule, a nucleic acid, protein therapeutic agents, acytokine or a growth factor.
 11. The conjugate of claim 1, wherein thetherapeutic agent is an anti-cancer agent.
 12. The conjugate of claim 1,wherein the therapeutic agent is an anti-angiogenic agent.
 13. Theconjugate of claim 1, wherein the therapeutic agent is selected fromabrin, ricin A, pseudomonas exotoxin shiga toxin, diphtheria toxin, atumor necrosis factor, α-interferon, γ-interferon, nerve growth factor,tissue factor and tissue factor variants, FAS-ligand platelet derivedgrowth factor, tissue plasminogen activator, interleukin-1 (IL-1),interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophagecolony stimulating factor (GMCSF), granulocyte colony stimulating factor(G-CSF), erythropoietin (EPO), nerve growth factor, fibroblast growthfactors (FGFs), and epidermal growth factor.
 14. The conjugate of claim1, wherein the therapeutic agent is selected from alkylating agents,toxins, antiproliferative agents, pro-apoptotic agents, pro-coagulants,cytotoxic nucleosides and tubulin binding agents.
 15. The conjugate ofclaim 1, wherein the therapeutic agent is selected from among thefollowing classes of drugs: a) anthracycline family of drugs, b) vincaalkaloid drugs, c) mitomycins, d) bleomycins, e) cytotoxic nucleosides,f) pteridine family of drugs. g) diynenes, h) estramustine, i)cyclophosphamide, j) taxanes, k) podophyllotoxins, l) maytansanoids, m)epothilones, and n) combretastatin and analogs, or pharmaceuticallyacceptable derivatives thereof.
 16. The conjugate of claim 1, whereinthe therapeutic agent is selected from among the following drugs: a)doxorubicin, b) carminomycin, c) daunorubicin, d) aminopterin, e)methotrexate, f) methopterin, g) dichloromethotrexate, h) mitomycin C,i) porfiromycin, j) 5-fluorouracil, k) 6-mercaptopurine, l) cytosinearabinoside, m) podophyllotoxin, n) etoposide, o) etoposide phosphate,p) melphalan, q) vinblastine, r) vincristine, s) leurosidine, t)vindesine, u) estramustine, v) cisplatin, w) cyclophosphamide, x) taxol,y) leurositte, z) 4-desacetylvinblastine, aa) epothilone B, bb)taxotere, cc) maytansanol, dd) epothilone A, and ee) combretastatin andanalogs; or a pharmaceutically acceptable derivative thereof.
 17. Theconjugate of claim 1, further comprising a linker between thetherapeutic agent and the peptidic substrate.
 18. The conjugate of claim17, wherein the linker comprises a carbohydrate, peptide, and/orhydrocarbon core.
 19. The conjugate of claim 17, wherein the linkercomprises: a biscarbonyl alkyl diradical whereby an amine moiety on thetherapeutic agent is connected with the linker unit to form an amidebond and the amino terminus of the peptidic substrate is connected withthe other end of the linker unit also forming an amide bond; or adiaminoalkyl diradical linker unit, whereby a carbonyl moiety on thetherapeutic agent is covalently attached to one of the amines of thelinker unit while the other amine of the linker unit is covalentlyattached to the C-terminus of the peptidic substrate; or is aself-eliminating linker of the following formulae:

where A is NH or O; D is N(H or alkyl) or O; R²⁵ is H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substitutedwith 1 or more, such as, for example, 1 to 3, substituents selected fromhalo, halo alkyl and alkyl, aralkyl, heteroaralkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, alk(en)(yn)ylgroups, halo, pseudohalo, cyano, hydroxy, haloalkyl and polyhaloalkyl,such as, for example, halo lower alkyl, especially trifluoromethyl,formyl, alkylcarbonyl, arylcarbonyl that optionally is substituted with1 or more, such as, for example, 1 to 3, substituents, for example,selected from halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy,alkoxycarbonyl, aryloxycarbonyl, aminoimino, alkoxycarbonylamino,aryloxycarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylamino-carbonyl, arylaminocarbonyl, diarylaminocarbonyl,aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy,alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino,alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro,mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano,isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl andarylaminosulfonyl; and y is an integer from 1 to
 3. 20. The conjugate ofclaim 17, wherein the linker is a diamine comprising a cyclic alkylenemoiety.
 21. The conjugate of claim 17, wherein the diamine contains abicycloalkylene moiety.
 22. The conjugate of claim 17, wherein thelinker selected from 1,4-bis(aminomethyl)cyclohexane,1,4-bis(aminomethyl)cycloheptane, 1,3-bis(aminomethyl)cyclopentane,1-amino-4-(aminomethyl)cyclohexane, 1,4-diaminocyclohexane and1,4-bis(aminomethyl)bicyclo[2.2.2]octane.
 23. The conjugate of claim 17,wherein the linker is a 1,ω-diaminoalkane.
 24. The conjugate of claim17, wherein the linker is a 1,3-diaminopropane.
 25. The conjugate ofclaim 17, wherein the linker is a 1,ω-dicarbonylalkane.
 26. Theconjugate of claim 25, wherein the linker selected from oxalic, malonic,succinic, glutaric, adipic and pivalic acids.
 27. The conjugate of claim1, wherein the peptidic substrate comprises P1 that is any amino acid.28. The conjugate of claim 27, wherein P1 is a naturally-occurring aminoacid.
 29. The conjugate of claim 27, wherein P1 is an amino acid with anaromatic, branched, or branched aromatic side chain.
 30. The conjugateof claim 1, wherein the peptidic substrate comprises P1, where P1 isselected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr. 31.The conjugate of claim 1, wherein: the peptidic substrate comprises aP1-P1′ bond; the P1-P1′ bond is the site of cleavage by a cell surfaceprotease; P1 is selected from Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile andThr; and P1′ is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib,Abu, Met or 6-aminohexanoyl.
 32. The conjugate of claim 1, wherein thepeptidic substrate comprises P1, wherein P1 is Arg, Lys or an Argsurrogate.
 33. The conjugate of claim 1, further comprising a P2 residueselected from Phe, Ser, Gly and Ala.
 34. The conjugate of claim 1,further comprising a P3 residue selected from Arg, Lys, Gln, Ser, Quatand Arg surrogates.
 35. The conjugate of claim 1, further comprising aP4 residue selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr,Glu, Phe and Val.
 36. The conjugate of claim 1, further comprising a P5residue selected from Arg and Arg surrogates.
 37. The conjugate of claim1, further comprising a P6 residue selected from Leu, Ile and Val. 38.The conjugate of claim 1, further comprising a P2′ residue selected fromGly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl.
 39. The conjugate of claim 1, further comprising a P3′residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib,Abu, Met and 6-aminohexanoyl.
 40. The conjugate of claim 1, wherein: thepeptidic substrate comprises a 5-mer that has the formula:P4-P3-P2-P1-P1′, wherein:P1 is selected from among Arg, Lys, Tyr, Phe,Trp, Ala, Val, Ile and Thr P2 is selected from Phe, Ser, Gly and Ala; P3is selected from Arg, Lys, Gln, Quat and Arg surrogates; P4 is selectedfrom Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val; andP1′ is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or6-aminohexanoyl.
 41. The conjugate of claim 40, wherein: the peptidicsubstrate optionally further comprises one or more of a P5 or P2′ aminoacid residue, wherein: P5 is Arg or an Arg surrogate; and P2′ isselected from among Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal,Aib, Abu, Met and 6-aminohexanoyl.
 42. The conjugate of claim 41,wherein: if the peptidic substrate comprises a P5 amino acid residue,then the peptidic substrate optionally further comprises a P6 amino acidresidue selected from Leu, Ile and Val; and if the peptidic substratecomprises a P2′ amino acid residue, then the peptidic substrateoptionally further comprises a P3′ amino acid residue selected from Gly,Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.43. The conjugate of claim 1, wherein: the therapeutic agent isconjugated directly or via a linker to the C terminus of the peptidicsubstrate.
 44. The conjugate of claim 1, wherein: the peptidic substratecomprises a cap at the N-terminus.
 45. The conjugate of claim 1, whereinthe cap is a hydrophilic blocking group.
 46. The conjugate of claim 1,wherein the cap is an acyl, sulfonyl or carbamoyl derivative.
 47. Theconjugate of claim 45, wherein the blocking group is selected from amonghydroxylated alkanoyls, polyhydroxylated alkanoyls, polyethyleneglycols, glycosylates, sugars and crown ethers.
 48. The conjugate ofclaim 43 that has formula I:X^(n)-(P6)_(m)-(P5)_(p)-(P4)_(l)-(P3)_(j)-(P2)_(i)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(L)_(n)-Zor a derivative thereof, wherein: Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows: l is 0 or 1; when l is0, j, i, p and m are 0; when l is 1, j is 0 or 1; when j is 0, i, p andm are 0; when j is 1, i is 0 or 1; when i is 0, p and m are 0; when i is1, p is 0 or 1; when p is 0, m is 0; when p is 1, m is 0 or 1; u, k andr are selected as follows: u is 0 or 1; when u is 0, k and r are 0; whenu is 1, k is 0 or 1; when k is 0, r is 0; when k is 1, r is 0 or 1; n is0 or 1; X^(n) is hydrogen, or an acyl, sulfonyl or carbamoyl cap; P1 isselected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr; P1′is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or6-aminohexanoyl; P2 is selected from Phe, Ser, Gly and Ala; P3 isselected from Arg, Lys, Gln, Ser, Quat and Arg surrogates; P4 isselected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe andVal; P5 is selected from Arg and Arg surrogates; P6 is selected fromLeu, Ile and Val; P2′ is selected from Gly, Ser, Ala, Leu, Ile, d-Ile,nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and P3′ is selectedfrom Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl.
 49. The conjugate of claim 48, wherein P1 is Arg, Lysor an Arg surrogate.
 50. The conjugate of claim 1, wherein: thetherapeutic agent is conjugated directly or via a linker to the Nterminus of the peptidic substrate.
 51. The conjugate of claim 50,wherein: the C-terminus of the peptidic substrate is a carboxylic acidor a carboxamide derivative.
 52. The conjugate of claim 50 that hasformula II:Z-(L)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-X^(c)or a derivative thereof, wherein: Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows: l is 0 or 1; when l is0, j, i, p and m are 0; when l is 1, j is 0 or 1; when j is 0, i, p andm are 0; when j is 1, i is 0 or 1; when i is 0, p and m are 0; when i is1, p is 0 or 1; when p is 0, m is 0; when p is 1, m is 0 or 1; u, k andr are selected as follows: u is 0 or 1; when u is 0, k and r are 0; whenu is 1, k is 0 or 1; when k is 0, r is 0; when k is 1, r is 0 or 1; n is0 or 1; X^(c), together with the carbonyl group of the amino acidresidue to which it is attached, forms a carboxylic acid or acarboxamide group; P1 is selected from among Arg, Lys, Tyr, Phe, Trp,Ala, Val, Ile and Thr; P1′ is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val,nVal, Aib, Abu, Met or 6-aminohexanoyl; P2 is selected from Phe, Ser,Gly and Ala; P3 is selected from Arg, Lys, Gln, Ser, Quat and Argsurrogates; P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu,Tyr, Glu, Phe and Val; P5 is selected from Arg and Arg surrogates; P6 isselected from Leu, Ile and Val; P2′ is selected from Gly, Ser, Ala, Leu,Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and P3′is selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Metand 6-aminohexanoyl.
 53. The conjugate of claim 52, wherein P1 is Arg,Lys or an Arg surrogate.
 54. The conjugate of claim 1, wherein a firsttherapeutic agent is attached, optionally via a first linker, to theN-terminus of the peptidic substrate; and a second therapeutic agent,which are the same or different from the first therapeutic agent, isattached, optionally via a second linker, which are the same ordifferent from the first linker, to the C-terminus of the peptidicsubstrate.
 55. The conjugate of claim 54 that has formula III:Z¹-(L¹)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(L²)_(v)-Z²or a derivative thereof, wherein: Z¹ and Z² are each therapeutic agentsand are the same or different; L¹ and L² are each linkers and are thesame or different; l, j, i, p and m are selected as follows: l is 0 or1; when l is 0, j, i, p and m are 0; when l is 1, j is 0 or 1; when j is0, i, p and m are 0; when j is 1, i is 0 or 1; when i is 0, p and m are0; when i is 1, p is 0 or 1; when p is 0, m is 0; when p is 1, m is 0 or1; u, k and r are selected as follows: u is 0 or 1; when u is 0, k and rare 0; when u is 1, k is 0 or 1; when k is 0, r is 0; when k is 1, r is0 or 1; n and v are each independently 0 or 1; P1 is selected from amongArg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr; P1′ is Gly, Ser, Ala,Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl; P2is selected from Phe, Ser, Gly and Ala; P3 is selected from Arg, Lys,Gln, Ser, Quat and Arg surrogates; P4 is selected from Pro, Arg, Ser,Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe and Val; P5 is selected from Argand Arg surrogates; P6 is selected from Leu, Ile and Val; P2′ isselected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu,Met and 6-aminohexanoyl; and P3′ is selected from Gly, Ser, Ala, Leu,Ile, nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.
 56. Theconjugate of claim 55, wherein P1 is Arg, Lys or an Arg surrogate. 57.The conjugate of claim 1, selected from:Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 46);Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 47);Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 48);Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 49);Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 50);Ac-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 51);Ac-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 52);Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 53);Ac-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 54);Ac-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 55);Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 56);Ac-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO:57);Ac-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 58);Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 59);Ac-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 60);Ac-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 61);Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 62);Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 63);Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 64);Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 65);Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 66);Ac-Arg-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 67);Ac-Pro-Arg-Phe-Lys-Ile-Ile-(therapeutic agent) (SEQ ID NO: 68);Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 69);Ac-Arg-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 70);Ac-Ser-Lys-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 71);Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 72);Ac-Arg-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 73);Ac-Pro-Arg-Phe-Arg-Ile-Ile-(therapeutic agent) (SEQ ID NO: 74);Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 75);Ac-Arg-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 76); andAc-Ser-Arg-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 77)pyroGlu-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 78);CH₃SO₂-D-HHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 79);N-p-tosyl-GIy-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 80);BenzoyI-Val-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 81);CH₃SO₂-D-HHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 82);N-α-Z-D-Arg-Gly-Arg-Ala-Ala-(therapeutic agent) in which Z isbenzyloxycarbonyl (SEQ ID NO: 83); pyroGlu-Gly-Arg-Ala-Ala-(therapeuticagent) (SEQ ID NO: 84); H-D-Ile-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQID NO: 85); Cbo-L-(γ)Glu(α-t-BuO)-Gly-Arg-Ala-Ala-(therapeutic agent) inwhich Cbo is carbobenzoxy (SEQ ID NO: 86);H-D-Pro-Phe-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 87);H-D-Val-Leu-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 88);Bz-Ile-Glu(γ-OH)-Gly-Arg-Ala-Ala-(therapeutic agent) in which Bz isbenzoyl (SEQ ID NO: 89); Bz-Ile-Glu(γ-OMe)-Gly-Arg-Ala-Ala-(therapeuticagent) (SEQ ID NO: 90); Bz-Pro-Phe-Arg-Ala-Ala-(therapeutic agent) (SEQID NO: 91); H-D-Phe-Pip-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 92);H-D-Val-Leu-Lys-Ala-Ala-(therapeutic agent) (SEQ ID NO: 93);H-D-Nle-HHT-Lys-Ala-Ala-(therapeutic agent) (SEQ ID NO: 94);Pyr-Arg-Thr-Lys-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 95);H-Arg-Gln-Arg-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 96);Boc-Gln-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 97);Z-Arg-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 98);H-D-HHT-Ala-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 99);H-D-CHT-Gly-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 100);MeSO₂-dPhe-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 101);δ-Z-D-Lys-Pro-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 102);CH₃SO₂-D-CHA-But-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 103);Ac-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 104);Ac-Arg-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 105);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-Ala-(therapeutic agent) (SEQ ID NO: 106);Ac-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO: 107);Ac-Arg-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO: 108);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Gly-Gly-(therapeutic agent) (SEQ ID NO: 109);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-(therapeutic agent) (SEQ ID NO: 110);Ac-Arg-Arg-Gln-Ser-Arg-Ile-(therapeutic agent) (SEQ ID NO: 111);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ala-Ile-(therapeutic agent) (SEQ ID NO: 112);Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:113); Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 114); Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQID NO: 115); Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Leu-(therapeutic agent)(SEQ ID NO: 116); Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent)(SEQ ID NO: 117); Ac-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent)(SEQ ID NO: 118); Ac-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ IDNO: 11 9); Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQID NO: 120); Ac-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 121); Ac-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:122); Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:123); Ac-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:124); Ac-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 125);Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 126);Ac-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 127);Ac-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 128);Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:129); Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 130); Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQID NO: 131); Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Leu-(therapeutic agent)(SEQ ID NO: 132); Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent)(SEQ ID NO: 133); Ac-Arg-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent)(SEQ ID NO: 134); Ac-Pro-Arg-Phe-Lys-Ser-Leu-(therapeutic agent) (SEQ IDNO: 135); Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 136); Ac-Arg-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:137); Ac-Ser-Lys-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 138);Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 139);Ac-Arg-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 140);Ac-Pro-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 141);Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 142);Ac-Arg-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 143);Ac-Ser-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 144);pyroGlu-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 145);CH₃SO₂-D-HHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 146);N-p-tosyl-Gly-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 147);Benzoyl-Val-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 148);CH₃SO₂-D-HHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 149);N-α-Z-D-Arg-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 150)(Z=benzyloxycarbonyl); pyroGlu-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQID NO: 151); H-D-Ile-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:152); Cbo-L-(γ)Glu(α-t-BuO)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 153) (Cbo=carbobenzoxy); H-D-Pro-Phe-Arg-Ser-Leu-(therapeutic agent)(SEQ ID NO: 154); H-D-Val-Leu-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 155); Bz-Ile-Glu(γ-OH)-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 156) (Bz=benzoyl); Bz-Ile-Glu(γ-OMe)-Gly-Arg-Ser-Leu-(therapeuticagent) (SEQ ID NO: 157); Benzoyl-Pro-Phe-Arg-Ser-Leu-(therapeutic agent)(SEQ ID NO: 158); H-D-Phe-Pip-Arg-Ser-Leu-(therapeutic agent) (SEQ IDNO: 159); H-D-Val-Leu-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO: 160);H-D-Nle-HHT-Lys-Ser-Leu-(therapeutic agent) (SEQ ID NO: 161);Pyr-Arg-Thr-Lys-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 162);H-Arg-Gln-Arg-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 163);Boc-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 164);Z-Arg-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 165);H-D-HHT-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 166);H-D-CHT-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 167);MeSO₂-dPhe-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 168);δ-Z-D-Lys-Pro-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 169);CH₃SO₂-D-CHA-But-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 170);Ac-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 171);Ac-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 172);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 173);Ac-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 174);Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 175);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 176);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 177);Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 178);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 179);Ac-Arg-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 180);Ac-Arg-Gln-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 181);Ac-Arg-Gln-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 182);Ac-Arg-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 183);Ac-Arg-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 184);Ac-Arg-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 185);Ac-Arg-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 186);Ac-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 187);Ac-Gln-Gly-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 188);Ac-Gln-Ala-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 189);Ac-Gln-Phe-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO: 190);Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:191); Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 192); Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent)(SEQ ID NO: 193); Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Ser-Leu-(therapeuticagent) (SEQ ID NO: 194);Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:195); Ac-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:196); Ac-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:197); Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 198); Ac-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 199); Ac-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:200); Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 201); Ac-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 202); Ac-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:203); Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 204); Ac-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 205); Ac-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:206); Ac-Leu-Arg-Ala-Quat-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 207); Ac-Leu-Arg-Ala-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent)(SEQ ID NO: 208); Ac-Leu-Arg-Ser-Quat-Gly-Arg-Ser-Ser-Leu-(therapeuticagent) (SEQ ID NO: 209);Ac-Leu-Arg-Ser-Quat-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:210); Ac-Leu-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 211); Ac-Arg-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 212); Ac-Pro-Arg-Phe-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:213); Ac-Leu-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 214); Ac-Arg-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 215); Ac-Ser-Lys-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:216); Ac-Leu-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 217); Ac-Arg-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 218); Ac-Pro-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:219); Ac-Leu-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 220); Ac-Arg-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 221); Ac-Ser-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:222); pyroGlu-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 223);CH₃SO₂-D-HHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 224);N-p-tosyl-Gly-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 225);Benzoyl-Val-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 226);CH₃SO₂-D-HHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 227);N-α-Z-D-Arg-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 228)(Z=benzyloxycarbonyl); pyroGlu-Gly-Arg-Ser-Ser-Leu-(therapeutic agent)(SEQ ID NO: 229); H-D-Ile-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 230); Cbo-L-(γ)Glu(α-t-BuO)-Gly-Arg-Ser-Ser-Leu-(therapeuticagent) (SEQ ID NO: 231) (Cbo=carbobenzoxy);H-D-Pro-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 232);H-D-Val-Leu-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 233);Bz-Ile-Glu(γ-OH)-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:234) (Bz=benzoyl); Bz-Ile-Glu(γ-OMe)-Gly-Arg-Ser-Ser-Leu-(therapeuticagent) (SEQ ID NO: 235); Benzoyl-Pro-Phe-Arg-Ser-Ser-Leu-(therapeuticagent) (SEQ ID NO: 236); H-D-Phe-Pip-Arg-Ser-Ser-Leu-(therapeutic agent)(SEQ ID NO: 237); H-D-Val-Leu-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQID NO: 238); H-D-Nle-HHT-Lys-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:239); Pyr-Arg-Thr-Lys-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:240); H-Arg-Gln-Arg-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:241); Boc-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 242);Z-Arg-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 243);H-D-HHT-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 244);H-D-CHT-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 245);MeSO₂-dPhe-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 246);δ-Z-D-Lys-Pro-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 247);CH₃SO₂-D-CHA-But-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 248);Ac-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 249);Ac-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 250);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:251); Ac-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 252);Ac-Arg-Arg-Gln-Ser-Arg-Leu-(therapeutic agent) (SEQ ID NO: 253);Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:254); Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:255); Ac-Arg-Arg-Gln-Ser-Arg-Ser-Leu-(therapeutic agent) (SEQ ID NO:256); Ac-Leu-Arg-Arg-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ IDNO: 257); Ac-Arg-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:258); Ac-Arg-Gln-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:259); Ac-Arg-Gln-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO:260); Ac-Arg-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 261);Ac-Arg-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 262);Ac-Arg-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 263);Ac-Arg-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 264);Ac-Gln-Ser-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 265);Ac-Gln-Gly-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 266);Ac-Gln-Ala-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 267); andAc-Gln-Phe-Arg-Ser-Ser-Leu-(therapeutic agent) (SEQ ID NO: 268).
 58. Theconjugate of claim 35, wherein P4 is selected from Pro, Arg, Ser, Ala,Lys, Gly, nLeu, Phe and Val.
 59. The conjugate of claim 35, wherein: P2,P3 and/or P4 is/are selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu,Leu, Tyr, GLu, Phe and Val.
 60. The conjugate of claim 35, wherein: P2,P3 and/or P4 is/are selected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu,Tyr, Glu, Leu Phe and Val; and P1 is any amino acid.
 61. The conjugateof claim 60, wherein P1 is a naturally-occurring amino acid.
 62. Theconjugate of claim 60, wherein P1 is an amimo acid with an aromatic,branched, or branched aromatic side chain.
 63. The conjugate of claim60, wherein P1 is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val,Ile and Thr.
 64. The conjugate of claim 60, wherein P1 is Arg, Lys or anArg surrogate.
 65. The conjugate of claim 1, wherein the protease islocated at the cell surface by virtue of a specific binding interactionwith a receptor therefor.
 66. The conjugate of claim 65, wherein thecell surface protease is urokinase plasminogen activator (u-PA) bound tourokinase plasminogen activator receptor (u-PAR).
 67. The conjugate ofclaim 1, that comprises a peptidic substrate of the formulaP6-P5-P4-P3-P2-P1-P1′-P2′-P3′, wherein each of P1, P2, P3, P4, P5, P6,P1′ and P2′ are selected from residues set forth in FIGS. 1 and 2, andP6, P5, P4, P2′ and P3′ are optional.
 68. The conjugate of claim 67,wherein: P6 is optional and is selected from L, V, R; P5 is optional andis selected from R, I, L; P4 is optional and is selected from G, C, V;P3 is selected from S, dS, P, A or G; P2 is selected from A or G; P1 isR; P1′ is S, V, M or nL; P2′ is optional and is selected S, L, A or V;and P3′ is optional and is L.
 69. A conjugate selected from among thoseset forth in FIGS. 1-5, wherein the therapeutic agent doxorubicin (Dox)or taxol (Tax) optionally is replaced with any therapeutic agent. 70.The conjugate of claim 65, wherein the therapeutic agent is a toxin, asmall organic molecule, a nucleic acid, protein therapeutic agents, acytokine or a growth factor.
 71. The conjugate of claim 65, wherein thetherapeutic agent is an anti-cancer agent.
 72. The conjugate of claim65, wherein the therapeutic agent is an anti-angiogenic agent.
 73. Theconjugate of claim 65, wherein the therapeutic agent is selected fromabrin, ricin A, pseudomonas exotoxin shiga toxin, diphtheria toxin, atumor necrosis factor, α-interferon, γ-interferon, nerve growth factor,tissue factor and tissue factor variants, FAS-ligand platelet derivedgrowth factor, tissue plasminogen activator, interleukin-1 (IL-1),interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte macrophagecolony stimulating factor (GMCSF), granulocyte colony stimulating factor(G-CSF), erythropoietin (EPO), nerve growth factor, fibroblast growthfactors (FGFs), and epidermal growth factor.
 74. The conjugate of claim65, wherein the therapeutic agent is selected from alkylating agents,toxins, antiproliferative agents, pro-apoptotic agents, pro-coagulants,cytotoxic nucleosides and tubulin binding agents.
 75. The conjugate ofclaim 65, wherein the therapeutic agent is selected from among thefollowing classes of drugs: a) anthracycline family of drugs, b) vincaalkaloid drugs, c) mitomycins, d) bleomycins, e) cytotoxic nucleosides,f) pteridine family of drugs. g) diynenes, h) estramustine, i)cyclophosphamide, j) taxanes, k) podophyllotoxins, l) maytansanoids, m)epothilones, and n) combretastatin and analogs, or pharmaceuticallyacceptable derivatives thereof.
 76. The conjugate of claim 65, whereinthe therapeutic agent is selected from among the following drugs: a)doxorubicin, b) carminomycin, c) daunorubicin, d) aminopterin, e)methotrexate, f) methopterin, g) dichloromethotrexate, h) mitomycin C,i) porfiromycin, j) 5-fluorouracil, k) 6-mercaptopurine, l) cytosinearabinoside, m) podophyllotoxin, n) etoposide, o) etoposide phosphate,p) melphalan, q) vinblastine, r) vincristine, s) leurosidine, t)vindesine, u) estramustine, v) cisplatin, w) cyclophosphamide, x) taxol,y) leurositte, z) 4-desacetylvinblastine, aa) epothilone B, bb)taxotere, cc) maytansanol, dd) epothilone A, and ee) combretastatin andanalogs; or a pharmaceutically acceptable derivative thereof.
 77. Theconjugate of claim 65, further comprising a linker between thetherapeutic agent and the peptidic substrate.
 78. The conjugate of claim65, wherein the linker comprises a carbohydrate, peptide, and/orhydrocarbon core.
 79. The conjugate of claim 77, wherein the linkercomprises: a biscarbonyl alkyl diradical whereby an amine moiety on thetherapeutic agent is connected with the linker unit to form an amidebond and the amino terminus of the peptidic substrate is connected withthe other end of the linker unit also forming an amide bond; or adiaminoalkyl diradical linker unit, whereby a carbonyl moiety on thetherapeutic agent is covalently attached to one of the amines of thelinker unit while the other amine of the linker unit is covalentlyattached to the C-terminus of the peptidic substrate; or is aself-eliminating linker of the following formulae:

where A is NH or O; D is N(H or alkyl) or O; R²⁵ is H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substitutedwith 1 or more, such as 1 to 3, substituents selected from, for example,halo, halo alkyl and alkyl, aralkyl, heteroaralkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, alk(en)(yn)ylgroups, halo, pseudohalo, cyano, hydroxy, haloalkyl and polyhaloalkyl,such as, for example, halo lower alkyl, including trifluoromethyl,formyl, alkylcarbonyl, arylcarbonyl that optionally is substituted with1 or more, such as, for example, 1 to 3, substituents selected from, forexample, halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy,alkoxycarbonyl, aryloxycarbonyl, aminoimino, alkoxycarbonylamino,aryloxycarbonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy,alkynyloxy, arylalkoxy, aminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl,arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino,alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro,mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano,isothiocyano, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl andarylaminosulfonyl; and y is an integer from 1 to
 3. 80. The conjugate ofclaim 77, wherein the linker is a diamine comprising a cyclic alkylenemoiety.
 81. The conjugate of claim 77, wherein the diamine contains abicycloalkylene moiety.
 82. The conjugate of claim 77, wherein thelinker selected from 1,4-bis(aminomethyl)cyclohexane,1,4-bis(aminomethyl)cycloheptane, 1,3-bis(aminomethyl)cyclopentane,1-amino-4-(aminomethyl)cyclohexane, 1,4-diaminocyclohexane and1,4-bis(aminomethyl)bicyclo[2.2.2]octane.
 83. The conjugate of claim 77,wherein the linker is a 1,ω-diaminoalkane.
 84. The conjugate of claim77, wherein the linker is a 1,3-diaminopropane.
 85. The conjugate ofclaim 77, wherein the linker is a 1,ω-dicarbonylalkane.
 86. Theconjugate of claim 77, wherein the linker is selected from oxalic,malonic, succinic, glutaric, adipic and pivalic acids.
 87. The conjugateof claim 1, wherein: the peptidic substrate comprises a P1-P1′ bond; theP1-P1′ bond is the site of cleavage by a cell surface protease; P1 isselected from Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr; and P1′ isGly, Ser, hSer, Thr, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu,Met or 6-aminohexanoyl.
 88. The conjugate of claim 87, furthercomprising a P2 residue selected from Phe, Ser, Gly, Ala, Ser(OMe),hSer, 1-methylHis, 3-methylHis, His, nVal, nLeu, Abu, (hS)Gly, Thr, Aib,CHA and Tyr.
 89. The conjugate of claim 88, further comprising a P3residue selected from Arg, Lys, Gin, Quat, Arg surrogates, Ser, Thr,hSer, dSer, Pro, (hS)Gly, Tyr, 4,4-dimethylThr, Asn, Met(O₂), Quat²,Quat³, Quat⁴ and Quat⁵.
 90. The conjugate of claim 89, furthercomprising a P4 residue selected from Pro, Arg, Ser, Ala, Lys, Gly,nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly, β-Ala, Cys(Me), Gln,t-butylGly and nVal.
 91. The conjugate of claim 90, further comprising aP5 residue selected from Ile, Arg and Arg surrogates.
 92. The conjugateof claim 91, further comprising a P6 residue selected from Val, Leu, Ileand Val.
 93. The conjugate of claim 87, further comprising a P2′ residueselected from Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu,Met, 6-aminohexanoyl, hCHA, CHA, hexylGly, allylGly and Phe.
 94. Theconjugate of claim 93, further comprising a P3′ residue selected fromGly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met,6-aminohexanoyl, CHA and allylGly.
 95. The conjugate of claim 94,further comprising a P4′ residue selected from Gly, Ser, Ala, Leu, Ile,nLeu, Val, nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly. 96.The conjugate of claim 95, wherein P4′ is Gly, Ser, Ala, Leu, Ile, nLeu,Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.
 97. The conjugate of claim96, wherein P4′ is Leu.
 98. The conjugate of claim 1, wherein: thepeptidic substrate comprises a 5-mer that has the formula:P4-P3-P2-P1-P1′, wherein: P1 is selected from among Arg, Lys, Tyr, Phe,Trp, Ala, Val, Ile and Thr; P2 is selected from Phe, Ser, Gly, Ala,Ser(OMe), hSer, 1-methylHis, 3-methylHis, His, nVal, nLeu, Abu, (hS)Gly,Thr, Aib, CHA and Tyr; P3 is selected from Arg, Lys, Gln, Quat, Argsurrogates, Ser, Thr, hSer, dSer, Pro, (hS)Gly, Tyr, 4,4-dimethylThr,Asn, Met(O₂), Quat², Quat³, Quat⁴ and Quat⁵; P4 is selected from Pro,Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly,β-Ala, Cys(Me), Gln, t-butylGly and nVal; and P1′ is Gly, Ser, hSer,Thr, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or6-aminohexanoyl.
 99. The conjugate of claim 40, wherein: the peptidicsubstrate optionally further comprises one or more of a P5 or P2′ aminoacid residue, wherein: P5 is Ile, Arg or an Arg surrogate; and P2′ isselected from among Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal,Aib, Abu, Met, 6-aminohexanoyl, hCHA, CHA, hexylGly, allylGly and Phe.100. The conjugate of claim 41, wherein: if the peptidic substratecomprises a P5 amino acid residue, then the peptidic substrateoptionally further comprises a P6 amino acid residue selected from Arg,Leu, Ile and Val; and if the peptidic substrate comprises a P2′ aminoacid residue, then the peptidic substrate optionally further comprises aP3′ amino acid residue selected from Gly, Ser, Ala, Leu, Ile, nLeu, Val,nVal, Aib, Abu, Met, 6-aminohexanoyl, CHA and allylGly; and if thepeptidic substrate comprises a P3′ amino acid residue, then the peptidicsubstrate optionally further comprises a P4′ amino acid residue selectedfrom Gly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met,6-aminohexanoyl, CHA and allylGly.
 101. The conjugate of claim 43 thathas formula IV:X^(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(P4′)_(s)-(L)_(n)-Zor a derivative thereof, wherein: Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows: l is 0 or 1; when l is0, j, i, p and m are 0; when l is 1, j is 0 or 1; when j is 0, i, p andm are 0; when j is 1, i is 0 or 1; when i is 0, p and m are 0; when i is1, p is 0 or 1; when p is 0, m is 0; when p is 1, m is 0 or 1; u, k, rand s are selected as follows: u is 0 or 1; when u is 0, k, r and s are0; when u is 1, k is 0 or 1; when k is 0, r and s are 0; when k is 1, ris 0 or 1; when r is 0, s is 0; when r is 1, s is 0 or 1; n is 0 or 1;X^(n) is hydrogen, or an acyl, sulfonyl or carbamoyl cap; P1 is selectedfrom among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr; P1′ is Gly,Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or6-aminohexanoyl; P2 is selected from Phe, Ser, Gly and Ala; P3 isselected from Arg, Lys, Gin, Ser, Quat and Arg surrogates; P4 isselected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe andVal; P5 is selected from Arg and Arg surrogates; P6 is selected fromLeu, Ile and Val; P2′ is selected from Gly, Ser, Ala, Leu, Ile, d-Ile,nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; P3′ is selected fromGly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl; and P4′ is selected from Gly, Ser, Ala, Leu, ile, nLeu,Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.
 102. The conjugate ofclaim 50 that has formula V:Z-(L)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(P4′)_(s)-X^(c)or a derivative thereof, wherein: Z is a therapeutic agent; L is alinker; l, j, i, p and m are selected as follows: l is 0 or 1; when l is0, j, i, p and m are 0; when l is 1, j is 0 or 1; when j is 0, i, p andm are 0; when j is 1, i is 0 or 1; when i is 0, p and m are 0; when i is1, p is 0 or 1; when p is 0, m is 0; when p is 1, m is 0 or 1; u, k, rand s are selected as follows: u is 0 or 1; when u is 0, k, r and s are0; when u is 1, k is 0 or 1; when k is 0, r and s are 0; when k is 1, ris 0 or 1; when r is 0, s is 0; when r is 1, s is 0 or 1; n is 0 or 1;X^(c), together with the carbonyl group of the amino acid residue towhich it is attached, forms a carboxylic acid or a carboxamide group; P1is selected from among Arg, Lys, Tyr, Phe, Trp, Ala, Val, Ile and Thr;P1′ is Gly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met or6-aminohexanoyl; P2 is selected from Phe, Ser, Gly and Ala; P3 isselected from Arg, Lys, Gln, Ser, Quat and Arg surrogates; P4 isselected from Pro, Arg, Ser, Ala, Lys, Gly, nLeu, Leu, Tyr, Glu, Phe andVal; P5 is selected from Arg and Arg surrogates; P6 is selected fromLeu, Ile and Val; P2′ is selected from Gly, Ser, Ala, Leu, Ile, d-Ile,nLeu, Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; P3′ is selected fromGly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl; and P4′ is selected from Gly, Ser, Ala, Leu, Ile, nLeu,Val, nVal, Aib, Abu, Met and 6-aminohexanoyl.
 103. The conjugate ofclaim 54 that has formula VI:Z¹-(L¹)_(n)-(P6)_(m)-(P5)_(p)-(P4)_(i)-(P3)_(j)-(P2)_(l)-P1-(P1′)_(u)-(P2′)_(k)-(P3′)_(r)-(P4′)_(s)-(L²)_(v)-Z²or a derivative thereof, wherein: Z¹ and Z² are each therapeutic agentsand are the same or different; L¹ and L² are each linkers and are thesame or different; l, j, i, p and m are selected as follows: l is 0 or1; when l is 0, j, i, p and m are 0; when l is 1, j is 0 or 1; when j is0, i, p and m are 0; when j is 1, i is 0 or 1; when i is 0, p and m are0; when i is 1, p is 0 or 1; when p is 0, m is 0; when p is 1, m is 0 or1; u, k, r and s are selected as follows: u is 0 or 1; when u is 0, k, rand s are 0; when u is 1, k is 0 or 1; when k is 0, r and s are 0; whenk is 1, r is 0 or 1; when r is 0, s is 0; when r is 1, s is 0 or 1; nand v are each independently 0 or 1; P1 is selected from among Arg, Lys,Tyr, Phe, Trp, Ala, Val, Ile and Thr; P1′ is Gly, Ser, Ala, Leu, Ile,d-Ile, nLeu, Val, nVal, Aib, Abu, Met or 6-aminohexanoyl; P2 is selectedfrom Phe, Ser, Gly and Ala; P3 is selected from Arg, Lys, Gin, Ser, Quatand Arg surrogates; P4 is selected from Pro, Arg, Ser, Ala, Lys, Gly,nLeu, Leu, Tyr, Glu, Phe and Val; P5 is selected from Arg and Argsurrogates; P6 is selected from Leu, Ile and Val; P2′ is selected fromGly, Ser, Ala, Leu, Ile, d-Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl; P3′ is selected from Gly, Ser, Ala, Leu, Ile, nLeu,Val, nVal, Aib, Abu, Met and 6-aminohexanoyl; and P4′ is selected fromGly, Ser, Ala, Leu, Ile, nLeu, Val, nVal, Aib, Abu, Met and6-aminohexanoyl.
 104. The conjugate of claim 1, selected from:Ac-R-Q-G-R-S-L-(therapeutic agent) (SEQ ID NO: 491);Ac-R-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 492);Ac-R-Q-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 493);Ac-R-Q-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 494);Ac-R-Q-G-R-S-F-(therapeutic agent) (SEQ ID NO: 495);Ac-R-Q-G-R-A-L-(therapeutic agent) (SEQ ID NO: 496);Ac-R-Q-G-R-A-L-(therapeutic agent) (SEQ ID NO: 497);Ac-R-Q-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 498);Ac-R-Q-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 499);Ac-R-Q-G-R-A-nV-(therapeutic agent) (SEQ ID NO: 500);Ac-R-Q-G-R-A-Cha-(therapeutic agent) (SEQ ID NO: 501);Ac-R-Q-G-R-A-F-(therapeutic agent) (SEQ ID NO: 502);Ac-R-N-G-R-S-L-(therapeutic agent) (SEQ ID NO: 503);Ac-R-N-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 504);Ac-R-Q-A-R-S-L-(therapeutic agent) (SEQ ID NO: 505);Ac-R-Q-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 506);Ac-R-Q-A-R-S-nV-(therapeutic agent) (SEQ ID NO: 507);Ac-R-Q-A-A-S-Cha-(therapeutic agent) (SEQ ID NO: 508);Ac-R-Q-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 509);Ac-R-Q-A-R-T-nL-(therapeutic agent) (SEQ ID NO: 510);Ac-R-Q-A-R-A-L-(therapeutic agent) (SEQ ID NO: 511);Ac-R-Q-A-R-A-nL-(therapeutic agent) (SEQ ID NO: 512);Ac-R-Q-A-R-A-nV-(therapeutic agent) (SEQ ID NO: 513);Ac-R-Q-A-R-A-Cha-(therapeutic agent) (SEQ ID NO: 514);Ac-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 515);Ac-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO: 516);Ac-R-Q-S-R-A-nL-(therapeutic agent) (SEQ ID NO: 517);Ac-R-Q-S-R-A-L-(therapeutic agent) (SEQ ID NO: 518);Ac-R-Q-S-R-A-nV-(therapeutic agent) (SEQ ID NO: 519);Ac-R-Q-S-R-A-Cha-(therapeutic agent) (SEQ ID NO: 520);Ac-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 521);Ac-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 522);Ac-R-Q-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 523);Ac-R-Q-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 524);Ac-R-Q-S-R-S-nV-(therapeutic agent) (SEQ ID NO: 525);Ac-R-Q-S-R-S-allylG-(therapeutic agent) (SEQ ID NO: 526);Ac-R-Q-S-R-S-Cha-(therapeutic agent) (SEQ ID NO: 527);Ac-R-Q-S-R-T-nL-(therapeutic agent) (SEQ ID NO: 528);Ac-R-Q-T-R-S-S-L-(therapeutic agent) (SEQ ID NO: 529);Ac-R-Q-T-R-S-L-(therapeutic agent) (SEQ ID NO: 530);Ac-R-N-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 531);Ac-R-Q-F-R-S-L-(therapeutic agent) (SEQ ID NO: 532);Ac-R-Q-F-R-S-nL-(therapeutic agent) (SEQ ID NO: 534);Ac-R-Q-F-R-S-nV-(therapeutic agent) (SEQ ID NO: 535);Ac-R-Q-F-R-S-nL-(therapeutic agent) (SEQ ID NO: 536);Ac-R-Q-F-R-S-Cha-(therapeutic agent) (SEQ ID NO: 537);Ac-R-Q-F-R-A-L-(therapeutic agent) (SEQ ID NO: 538);Ac-R-Q-F-R-A-nL-(therapeutic agent) (SEQ ID NO: 539);Ac-R-Q-F-R-A-nV-(therapeutic agent) (SEQ ID NO: 540);Ac-R-Q-F-R-A-Cha-(therapeutic agent) (SEQ ID NO: 541);Ac-Q-S-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 542);MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO: 483);MeOCO-Quat3-G-R-S-L-(therapeutic agent) (SEQ ID NO: 484);MeOCO-Quat-G-R-S-L-(therapeutic agent) (SEQ ID NO: 485);MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO: 486);MeOCO-Quat5-G-R-S-L-(therapeutic agent) (SEQ ID NO: 487);MeOCO-Quat2-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 488);MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO: 489);MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO: 490);Ac-Q-G-R-S-L-(therapeutic agent) (SEQ ID NO: 445);Ac-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 446);Ac-Q-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 447);Ac-N-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 448);Ac-Q-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 449);Ac-Q-G-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 450);Ac-Q-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 451);Ac-Q-G-R-S-S-allylG-(therapeutic agent) (SEQ ID NO: 452);Ac-Q-G-R-S-S-allylG-(therapeutic agent) (SEQ ID NO: 453);Ac-Q-A-R-S-L-(therapeutic agent) (SEQ ID NO: 454);Ac-Q-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 455);Ac-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 456);Ac-Q-S-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 457);Ac-Q-S-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 458);Ac-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 459);Ac-Q-T-R-S-S-L-(therapeutic agent) (SEQ ID NO: 460);Ac-Q-Aib-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 461);Ac-Q-Aib-R-S-S-L-(therapeutic agent) (SEQ ID NO: 462);Ac-Q-Abu-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 463);Ac-Q-Abu-R-S-S-L-(therapeutic agent) (SEQ ID NO: 464);Ac-Q-Cha-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 465);Ac-Q-F-R-S-L-(therapeutic agent) (SEQ ID NO: 466);Ac-Q-F-R-S-S-L-(therapeutic agent) (SEQ ID NO: 467);Ac-Q-Y-R-S-S-L-(therapeutic agent) (SEQ ID NO: 468);Ac-R-G-R-S-L-(therapeutic agent) (SEQ ID NO: 469);Ac-R-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 470);Ac-R-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 471);Ac-R-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 472);Ac-R-A-R-S-L-(therapeutic agent) (SEQ ID NO: 473);Ac-R-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 474);Ac-R-S-R-S-L-(therapeutic agent) (SEQ ID NO: 475);Ac-R-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 476);Ac-R-S-RS-Cha-(therapeutic agent) (SEQ ID NO: 477);Ac-R-S-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 478);Ac-R-F-R-S-L-(therapeutic agent) (SEQ ID NO: 479);Ac-R-F-R-S-Cha-(therapeutic agent) (SEQ ID NO: 480);Ac-Y-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 481);Ac-M(O2)-S-R-S-L-(therapeutic agent) (SEQ ID NO: 482);Ac-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 105);Ac-R-R-Q-S-R-I-(therapeutic agent) (SEQ ID NO: 610);Ac-R-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 543);Ac-R-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 544);Ac-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 545);Ac-R-G-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 546);Ac-R-G-S-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 547);Ac-R-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 548);Ac-I-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 549);Ac-R-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO: 108);Ac-R-R-Q-S-R-I-(therapeutic agent) (SEQ ID NO: 111);Ac-L-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 106);Ac-L-R-R-Q-S-R-G-G-(therapeutic agent) (SEQ ID NO: 109);Ac-L-R-R-Q-S-R-A-(therapeutic agent) (SEQ ID NO: 110);Ac-L-R-R-Q-S-R-A-I-(therapeutic agent) (SEQ ID NO: 112);Ac-L-R-R-Q-S-R-A-I-(therapeutic agent) (SEQ ID NO: 611);Ac-L-R-R-Q-S-R-S-S-L-(therapeutic agent) (SEQ ID NO: 550);Ac-L-R-R-Q-S-R-S-L-(therapeutic agent) (SEQ ID NO: 551);Ac-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 362);Ac-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 363);Ac-S-G-R-S-S-S-L-(therapeutic agent) (SEQ ID NO: 364);Ac-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 365);Ac-S-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 366); isomer 1Ac-S-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 367); isomer 2Ac-S-G-R-S-G(hex)-(therapeutic agent) (SEQ ID NO: 368);Ac-S-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 369);Ac-S-G-R-S-hCha-(therapeutic agent) (SEQ ID NO: 370);Ac-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 371);Ac-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 372);Ac-S-S-R-S-nL-(therapeutic agent) (SEQ ID NO: 373);Ac-T-G-R-S-Abu-(therapeutic agent) (SEQ ID NO: 374);Ac-T-G-R-S-L-(therapeutic agent) (SEQ ID NO: 375);Ac-T-G-R-S-nV-(therapeutic agent) (SEQ ID NO: 376);Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 377);Ac-T-G-R-S-G(hex)-(therapeutic agent) (SEQ ID NO: 378);Ac-T-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 379);Ac-T-G-R-S-hCha-(therapeutic agent) (SEQ ID NO: 380);Ac-T-G-R-T-Abu-(therapeutic agent) (SEQ ID NO: 381);Ac-T-G-R-hS-nL-(therapeutic agent) (SEQ ID NO: 382);Ac-T-G-R-Abu-nL-(therapeutic agent) (SEQ ID NO: 383);Ac-T-G-R-Abu-nV-(therapeutic agent) (SEQ ID NO: 384);Ac-T-G-F(Gn)-S-nL-(therapeutic agent) (SEQ ID NO: 385);Ac-T-G-F(Gn)-S-Cha-(therapeutic agent) (SEQ ID NO: 386);Ac-T-G-F(Gn)-Abu-nV-(therapeutic agent) (SEQ ID NO: 387);Ac-T-G-K(alloc)-S-nL-(therapeutic agent) (SEQ ID NO: 388);Ac-T-G-K-S-nL-(therapeutic agent) (SEQ ID NO: 389);Ac-T-G-hR-S-nL-(therapeutic agent) (SEQ ID NO: 390);Ac-(hS)G-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 391);MeOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 392);PhSO2-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 393);MeOEtCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 394);Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 395);4-oxo-Pentanoyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 396);3,4-MethyldioxyPhAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 397);2-PyridylAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 398);PhOAc-Ac-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 399);L-3-PhLactyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 400);MeOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 401);PhAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 402);MeOEtOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 403);MeOEtOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 404);HOOCButa-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 405);Z-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 406);EtOCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 407);βA-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 408);Pent-4-ynoyl-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 409);NapAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 410);iBoc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 411);HOAc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 412);MeSucc-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 413);N,N-diMeGly-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 414);Succ-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 415);HCO-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 416);Ac-T-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 417);Ac-T-A-F(Gn)-S-nL-(therapeutic agent) (SEQ ID NO: 418);Ac-T-A-R-Abu-nV-(therapeutic agent) (SEQ ID NO: 419);Ac-T-A-R-S-Abu-(therapeutic agent) (SEQ ID NO: 420);Ac-T-A-R-T-Abu-(therapeutic agent) (SEQ ID NO: 421);Ac-T-S(O-Me)-R-S-nL-(therapeutic agent) (SEQ ID NO: 422);Ac-T-hS-R-S-nL-(therapeutic agent) (SEQ ID NO: 423);Ac-T-(1-Me)H-R-S-nL-(therapeutic agent) (SEQ ID NO: 424);Ac-T-(3-Me)H-R-S-nL-(therapeutic agent) (SEQ ID NO: 425);Ac-T-H-R-S-nL-(therapeutic agent) (SEQ ID NO: 426);Ac-T-Sar-R-S-nL-(therapeutic agent) (SEQ ID NO: 427);Ac-T-nV-R-S-nL-(therapeutic agent) (SEQ ID NO: 428);Ac-T-nL-R-S-nL-(therapeutic agent) (SEQ ID NO: 429);Ac-T-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 430);Ac-T-Abu-R-S-nL-(therapeutic agent) (SEQ ID NO: 431);Ac-4,4diMeThr-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 432);Ac-hS-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 433);Ac-hS-G-R-hS-Cha-(therapeutic agent) (SEQ ID NO: 434);Ac-hS-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 435);Ac-hS-G-R-T-Cha-(therapeutic agent) (SEQ ID NO: 436);Ac-hS-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 437);Ac-N-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 438);Ac-Y-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 439);Ac-Y-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 440);Ac-Q-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 441);Ac-Q-G-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 442);Ac-L-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 573);Ac-L-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 342);Ac-L-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 343);Ac-L-R-G-S-G-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 344);Ac-L-R-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 345);Ac-L-R-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO: 574);Ac-L-R-G-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 346);Ac-L-R-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 347);Ac-L-R-G-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 348);Ac-L-R-G-S-A-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 349);Ac-L-R-G-S-A-R-S-S-nL-(therapeutic agent) (SEQ ID NO: 350);Ac-V-I-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 351);Ac-V-I-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 352);Ac-V-I-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 353);Ac-V-I-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO: 354);Ac-V-I-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO: 355);Ac-V-I-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 356);Ac-V-I-V-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 357);Ac-V-I-V-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 358);Ac-V-I-V-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 359);Ac-R-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 360);Ac-R-R-nV-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 361);Ac-R-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO: 309);Ac-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 310);Ac-R-G-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 311);Ac-R-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 312);Ac-R-G-S-G-R--S-nL-(therapeutic agent) (SEQ ID NO: 313);Ac-R-G-S-G-R-A-nL-(therapeutic agent) (SEQ ID NO: 314);Ac-R-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 315);Ac-R-G-S-G-R-S-Cha-(therapeutic agent) (SEQ ID NO: 316);Ac-R-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 317);Ac-R-G-S-A-R-S-Cha-(therapeutic agent) (SEQ ID NO: 318);Ac-R-G-S-A-R-S-S-(therapeutic agent) (SEQ ID NO: 319);Ac-R-G-S-A-R-S-nV-(therapeutic agent) (SEQ ID NO: 320);Ac-R-G-S-A-R-S-S-nV-(therapeutic agent) (SEQ ID NO: 321);Ac-R-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 322);Ac-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 323);Ac-R-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 324);Ac-R-C(Me)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 325);Ac-R-L-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 326);Ac-R-V-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 327);Ac-R-V-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 328);Ac-R-nL-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 329);Ac-R-G(tBu)-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 330);Ac-R-L-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 331);Ac-R-V-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 332);Ac-R-nL-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 333);Ac-I-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 334);Ac-I-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 335);Ac-I-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 336);Ac-I-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO: 337);Ac-I-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO: 338);Ac-I-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 339);Ac-I-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 340);Ac-I-V-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 341);Ac-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 585);Ac-G-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 277);Ac-G-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 278);Ac-G-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 279);Ac-G-S-G-R-L-(therapeutic agent) (SEQ ID NO: 280);Ac-G-S-G-(4-guan)Phg-S-L-(therapeutic agent) (SEQ ID NO: 281);Ac-G-S-G-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 282);Ac-G-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 283);Ac-G-S-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 284);Ac-G-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 285);Succ-bA-T-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 286);Ac-G-T-G-R-S-hCha-(therapeutic agent) (SEQ ID NO: 287);Ac-G-hS-G-R-S-nL-(therapeutic agent) (SEQ ID NO: 288);Ac-G-dS-A-R-S-A-(therapeutic agent) (SEQ ID NO: 289);Ac-G-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 290);Ac-G-S-A-R-S-S-Cha-(therapeutic agent) (SEQ ID NO: 291);Ac-G-S-A-R-S-S-L-(therapeutic agent) (SEQ ID NO: 292);Ac-G-S-A-R-A-S-L-(therapeutic agent) (SEQ ID NO: 293);Ac-V-S-G-R-S-L-(therapeutic agent) (SEQ ID NO: 294);Ac-V-S-G-R-A-L-(therapeutic agent) (SEQ ID NO: 295);Ac-V-S-G-R-A-S-L-(therapeutic agent) (SEQ ID NO: 296);Ac-V-S-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 297);Ac-V-S-A-R-M-A-(therapeutic agent) (SEQ ID NO: 298);Ac-V-S-A-R-nL-A-(therapeutic agent) (SEQ ID NO: 299);Ac-V-S-A-R-S-nL-(therapeutic agent) (SEQ ID NO: 300);Ac-V-S-A-R-S-L-(therapeutic agent) (SEQ ID NO: 301);Ac-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 302);Ac-(Me)C-P-G-R-V-V-(therapeutic agent) (SEQ ID NO: 303);Ac-C(Me)-P-G-R-A-L-(therapeutic agent) (SEQ ID NO: 304);Ac-C(Me)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 305);Ac-C(Me)-P-A-R-S-L-(therapeutic agent) (SEQ ID NO: 306);Ac-C(Me)-P-A-R-A-S-L-(therapeutic agent) (SEQ ID NO: 307);Ac-G(tBu)-P-G-R-S-L-(therapeutic agent) (SEQ ID NO: 308);Ac-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 552);Ac-Q-S-R-S-A-(therapeutic agent) (SEQ ID NO: 553);Ac-Q-S-R-S-G-(therapeutic agent) (SEQ ID NO: 554);Ac-R-S-R-A-A-(therapeutic agent) (SEQ ID NO: 555);Ac-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 556);Ac-R-Q-S-R-S-A-(therapeutic agent) (SEQ ID NO: 557);Ac-R-Q-S-R-S-A-A-(therapeutic agent) (SEQ ID NO: 558);Ac-R-G-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 559);Ac-S-G-R-A-A-(therapeutic agent) (SEQ ID NO: 560);Ac-S-G-R-S-A-(therapeutic agent) (SEQ ID NO: 561);Ac-S-G-R-S-S-A-(therapeutic agent) (SEQ ID NO: 562);Ac-S-G-R-A-S-A-(therapeutic agent) (SEQ ID NO: 563);Ac-S-G-R-S-G-(therapeutic agent) (SEQ ID NO: 564);Ac-S-G-R-S-S-G-(therapeutic agent) (SEQ ID NO: 565);Ac-S-G-R-S-G-A-(therapeutic agent) (SEQ ID NO: 566);Ac-S-G-R-S-G-G-(therapeutic agent) (SEQ ID NO: 567);Ac-G-T-G-R-S-G-G-(therapeutic agent) (SEQ ID NO: 568);Ac-G-S-G-R-S-G-G-(therapeutic agent) (SEQ ID NO: 243)Ac-L-R-R-Q-S-R-A-A-(therapeutic agent) (SEQ ID NO: 597);MeSO2-dA(Chx)-Abu-R-S-L-(therapeutic agent) (SEQ ID NO: 598);Ac-R-A-R-S-L-(therapeutic agent) (SEQ ID NO: 599);Ac-dA(Chx)-Abu-R-S-L-(therapeutic agent) (SEQ ID NO: 600);Ac-dA(Chx)-Abu-R-S-S-L-(therapeutic agent) (SEQ ID NO: 601);Ac-Q-G-R-S-S-L-(therapeutic agent) (SEQ ID NO: 602);MeOCO-dhF-P(OH)-R-S-S-L-(therapeutic agent) (SEQ ID NO: 603);MeOCO-Quat4-G-R-S-L-(therapeutic agent) (SEQ ID NO: 604);Ac-dCha-P(OH)-R-S-S-L-(therapeutic agent) (SEQ ID NO: 605);Ac-dCha-Abu-R-S-S-A-(therapeutic agent) (SEQ ID NO: 606);MeOCO-Quat2-G-R-S-L-(therapeutic agent) (SEQ ID NO: 607);MeOCO-Quat3-G-R-S-L-(therapeutic agent) (SEQ ID NO: 608); andMeOCO-Quat-G-R-S-L-(therapeutic agent) (SEQ ID NO: 609).
 105. Theconjugate of claim 35, wherein P4 is selected from Pro, Arg, Ser, Ala,Lys, Gly, nLeu, Leu, Tyr, Glu, Phe, Val, N,N-dimethylGly, β-Ala,Cys(Me), Gln, t-butylGly and nVal.
 106. The conjugate of claim 1, thatcomprises a peptidic substrate of the formulaP6-P5-P4-P3-P2-P1-P1′-P2′-P3′-P4′, wherein each of P1, P2, P3, P4, P5,P6, P1′ and P2′ are selected from residues set forth in FIGS. 1 and 2,and P6, P5, P4, P2′, P3′ and P4′ are optional.
 107. The conjugate ofclaim 67, wherein: P6 is optional and is selected from L, V, R; P5 isoptional and is selected from R, I, L; P4 is optional and is selectedfrom G, C, V; P3 is selected from S, dS, P, A or G; P2 is selected fromA or G; P1 is R; P1′ is S, V, M or nL; P2′ is optional and is selectedS, L, A or V; P3′ is optional and is L; and P4′ is optional and is L.108. A conjugate, comprising a therapeutic agent and a nucleic acidsubstrate linked thereto via a peptidic linker, wherein the peptidiclinker is proteolytically cleaved by a cell surface protease or asoluble, released or shed form thereof, to liberate the therapeuticagent, wherein the conjugate is not substantially cleaved by plasmin orprostate specific antigen (PSA).
 109. The conjugate of claim 108,wherein the nucleic acid is DNA.
 110. The conjugate of claim 108,wherein the nucleic acid is RNA.
 111. The conjugate of claim 108,wherein the nucleic acid is double-stranded RNA.
 112. The conjugate ofclaim 67, wherein: P6 is optional and is selected from L, V, R; P5 isoptional and is selected from R, I, L; P4 is optional and is selectedfrom G, C, V; P3 is selected from S, dS, P, A or G; P2 is selected fromA or G; P1 is R; P1′ is T, Abu, hS, nV or A; P2′ is optional and isselected S, L, A or V; P3′ is optional and is L, nL, nV, G(hex),G(allyl), CHA, hCHA, or Abu; and P4′ is optional and is L, nL, nV,G(hex), G(allyl), CHA, hCHA, or Abu.
 113. The conjugate of claim 67,wherein: P6 is optional and is selected from L, V, R; P5 is optional andis selected from R, I, L; P4 is optional and is selected from G, C, V;P3 is selected from S, dS, P, A or G; P2 is selected from A or G; P1 isR; P1′ is S, G or A; P2′ is optional and is selected G or A; P3′ isoptional and is L, nL, nV, G(hex), G(allyl), CHA, hCHA, or Abu; and P4′is optional and is L, nL, nV, G(hex), G(allyl), CHA, hCHA, or Abu. 114.The conjugate of claim 1, wherein the therapeutic agent is taxol. 115.The conjugate of claim 1, wherein the therapeutic agent is doxorubicin.116. A method of treatment of a disease, comprising administering aconjugate of claim 1 to a subject, wherein the disease is a cell-surfaceprotease-associated disease.
 117. The method of claim 116, wherein thedisease is selected from the group consisting of autoimmune disesases,inflammatory diseases, infectious diseases and endocrine diseases. 118.The method of claim 116, wherein the disease is a proliferative disease.119. A method of treatment of a cell-surface protease-associateddisease, comprising administering a conjugate, comprising a therapeuticagent and a peptidic substrate linked thereto optionally via a linker,wherein the peptidic substrate is proteolytically cleaved by a cellsurface protease or a soluble, released or shed form thereof to liberatethe therapeutic agent, to a subject exhibiting symptoms of acell-surface protease-associated disorder.
 120. The method of claim 119,wherein the disease is selected from the group consisting of autoimmunedisesases, inflammatory diseases, infectious diseases and endocrinediseases.
 121. The method of claim 119, wherein the disease is aproliferative disease.
 122. The method of claim 114, wherein the subjectis a mammal.
 123. The method of claim 120, wherein the mammal is ahuman.
 124. The method of claim 118, wherein the disease is cancer. 125.The method of claim 118, wherein the disease is selected from oculardisorders, cardiovascular disorders, chronic inflammatory diseases,wounds, circulatory disorders, dermatological disorders and cancer. 126.The method of claim 118, wherein the disease is selected from rheumatoidarthritis, psoriasis, diabetic retinopathies, recurrence of pterygii,scarring from excimer laser surgery, scarring from glaucoma filteringsurgery, macular degeneration anterior eye, crest syndromes, solidneoplasms and vascular tumors.
 127. The method of claim 118, wherein thedisease is selected from lung cancer, colon cancer, pancreatic cancer,esophageal cancer, breast cancer, ovarian cancer, prostate cancer,melanoma and Kaposi's sarcoma.
 128. The method of claim 116, wherein thetherapeutic agent is taxol.
 129. The method of claim 116, wherein thetherapeutic agent is doxorubicin.
 130. A pharmaceutical composition,comprising the conjugate of claim 1 or a pharmaceutically acceptablederivative thereof, in a pharmaceutically acceptable carrier.
 131. Thepharmaceutical composition of claim 130 that is formulated for singledosage administration.
 132. An article of manufacture, comprisingpackaging material, the conjugate of claim 1, or a pharmaceuticallyacceptable derivative thereof, contained within packaging material,which is used for treatment, prevention or amelioration of one or moresymptoms associated with cell-surface protease-associated diseases ordisorders, and a label that indicates that the conjugate orpharmaceutically acceptable derivative thereof is used for treatment,prevention or amelioration of one or more symptoms associated withcell-surface protease-associated diseases or disorders.
 133. A method ofpreparing a conjugate of claim 1, comprising: a) synthesizing thepeptidic substrate; b) optionally capping the peptidic substrate oneither the N-terminus or the C-terminus; c) optionally linking thenon-capped terminus of the peptidic substrate to a linker; d) couplingthe peptidic substrate to a therapeutic agent, optionally via thelinker, to form a conjugate; and e) optionally, deprotecting theconjugate, if protected.
 134. The method of claim 133, wherein, prior tostep a), the method comprises a step of identifying a peptidic substratefor the protease.
 135. A method, comprising: a) selecting a disease; b)identifying a cell involved in the disease process or a cell in thevicinity of the cell involved in the disease process; and c) identifyinga cell surface protease on the cell, thereby identifying proteases totarget conjugates for treatment of diseases.
 136. The method of claim135, further comprising preparing a conjugate that targets the protease.